Статті в журналах: "Hematology Analyzer reports"

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Slim, Christiaan L., Brigitte A. Wevers, Martijn W. H. J. Demmers, Gabriella Lakos, Johannes J. M. L. Hoffmann, Henk J. Adriaansen, Jurgen A. Kooren, and Huibert Storm. "Multicenter performance evaluation of the Abbott Alinity hq hematology analyzer." Clinical Chemistry and Laboratory Medicine (CCLM) 57, no. 12 (November 26, 2019): 1988–98. http://dx.doi.org/10.1515/cclm-2019-0155.

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Abstract Background Alinity hq (Abbott) is a new high-throughput hematology analyzer that exclusively employs optical principles for detecting and enumerating blood cells. It reports 29 parameters, including a six-part white blood cell (WBC) differential. The aim of this multicenter study was to evaluate the analytical and clinical performance of the Alinity hq. Methods Complete blood count (CBC) results and morphological flagging were compared to that of CELL-DYN Sapphire (Abbott) and 2 × 200-cell manual differential results, on 1473 whole-blood samples from a well-defined patient population from three different clinical laboratories in the Netherlands. In addition, within-run and within-laboratory precision, linearity, limit of quantitation, carryover and sample stability were assessed. External quality assessment samples were also evaluated. Results Data analysis demonstrated strong concordance of Alinity hq results with those of CELL-DYN Sapphire for all CBC parameters, except for basophil granulocytes. Alinity hq WBC differential showed high level of agreement with manual differential results and exhibited a better agreement with manual basophil results than CELL-DYN Sapphire. The sensitivity of the Alinity hq Blast flag was 57.6%, equal to the 57.6% sensitivity of the CELL-DYN Sapphire’s Blast Alert. When considering samples with ≥5% blasts, the sensitivity of the Alinity hq Blast flag was 70.0%. Analytical performance of Alinity hq was shown to be consistent with state-of-the-art (SOTA) performance characteristics. Conclusions Alinity hq CBC measurands demonstrated good overall agreement with results obtained with CELL-DYN Sapphire, as well as manual WBC differential. The analytical and clinical performance characteristics of Alinity hq make it well suited for clinical laboratories.

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Sarafyniuk, L. A., T. V. Shevchuk, S. O. Ivanov, and N. A. Shevchuk. "Specific features of blood parameters in volleyball players and wrestlers in preparatory period of training cycle." Reports of Vinnytsia National Medical University 26, no. 2 (June 14, 2022): 202–8. http://dx.doi.org/10.31393/reports-vnmedical-2022-26(2)-05.

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Annotation. Study of modern laboratory markers of structural and functional disturbances of muscle tissue in athletes, reflecting energy metabolism, paravertebral muscle damage, and being an indicator of body performance and muscle activity, is of undeniable practical importance for modern sports medicine. The aim of the study was to determine clinical and biochemical parameters of blood in volleyball players and wrestlers in assessment of structural and functional changes in skeletal muscles. Blood examination was carried out in 26 volleyball players and 25 middleweight Greco-Roman wrestlers as part of repeated comprehensive medical examination being conducted at the Department of Physical Education of Vinnytsia National Pirogov Memorial Medical University. Eligible subjects included athletes 17 to 21years of age having first adult category to master of sports and being in preparatory period of annual training macrocycle. The athletes were examined in the morning, on empty stomach, not less than 12 hours after training. The control group consisted of 25 practically healthy students having moderate physical activity. Clinical blood indices were determined by conductometric method on an automatic hematology analyzer ABX HORIBA PENTRA 60 C + (France). Hormonal studies were carried out by immunochemiluminescence method on automatic analyzer “ACCESS-2”, Bekchman Coulter (USA). Biochemical studies were performed using an automatic analyzer AU-480, Bekchman Coulter (USA). Electrolyte content was determined by ion-selective electrode technology on Medica electrolyte analyzer in EasyElectrolytes™, using lithium heparin vacuum system. Glucose levels were determined on automatic analyzer Biosen (Germany). Statistical processing was done using the program “Statistica 5.5”. Significance of differences between the variables was determined by Mann-Whitney U-test. The following serum humoral factors were found to be of great significance in assessment of structural and functional changes in skeletal muscles in volleyball players and wrestlers: the number of large immature cells of monocytes and platelets, electrolyte content, concentration of creatine phosphokinase and lactate dehydrogenase, creatinine level, as well as triglycerides and lactate levels. Establishing blood biomarkers should be an integral part of scientific and practical monitoring of health status in team athletes and wrestlers.

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Taha, Elmutaz H., Mohammed Elshiekh, Abdelrahim Alborai, Elnagi Y. Hajo, Abdelmohisen Hussein, Kamal M. Awad, Ibrahim A. Ali, and Omer A. Musa. "Normal range of white blood cells and differential count of Sudanese in Khartoum state." International Journal of Advances in Medicine 5, no. 4 (July 23, 2018): 784. http://dx.doi.org/10.18203/2349-3933.ijam20183116.

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Background: The normal physiological range for white blood cells and differential count are essential for diagnosis, treatment, follow up and screening. This study aimed at establishing the reference ranges of WBCs and differential count in Sudanese people.Methods: The present study included 444 healthy adult Sudanese from both sexes with age range of 20 – 60 years. Blood samples were obtained from brachial veins and drawn in EDTA tubes. WBCs and differential count were analyzed using Sysmex KX-21 automated hematology analyzer. Full clinical examination was performed, weight and height were measured, and BMI was calculated.Results: The mean WBC count was 5.1±1.5×103/ µl with a range of 3.6 ×103/µl to 6.6 ×103/µl. The mean WBCs count for males and females were 4.969×103/µl and 5.138×103/µl respectively. Neutrophils count was 2.430×103/µl (47%) and mean for lymphocyte count was 2.116×103/µl (41.1%).Conclusions: WBCs count was directly proportional to BMI. The WBCs count of Sudanese people was lower than that of Caucasians and similar to reports from other African countries.

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PANOUSIS (Ν. ΠΑΝΟΥΣΗΣ), N., Z. POLIZOPOULOU (Ζ. ΠΟΛΥΖΟΠΟΥΛΟΥ), P. FORTOMARIS (Π. ΦΟΡΤΟΜΑΡΗΣ), A. PAPASTERIADIS (Α. ΠΑΠΑΣΤΕΡΙΑΔΗΣ), and H. KARATZIAS (Χ. ΚΑΡΑΤΖΙΑΣ). "Computer-aided complete blood counts in dairy cattle of the Thessaloniki region: A clinical study." Journal of the Hellenic Veterinary Medical Society 52, no. 1 (January 31, 2018): 32. http://dx.doi.org/10.12681/jhvms.15404.

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This study reports the findings of complete blood counts (CBC), performed in 100 Friesian dairy cattle of various cattle farms in the Thessaloniki region. Farm selection was done with the criteria of proper management standards, such as housing, feeding schedules, vaccinations and deworming. According to their age and reproductive status, the animals were allocated in following five groups:• Group I: calves 0-3 months old.• Group II: calves 3-14 months old.• Group III: cows 14 months-3 years old.• Group IV: cows older than 3 years.• Group V: cows in the dry period.Analysis included the determination of hematocrit, hemoglobin, leucocyte and platelet counts with the aid of the veterinary hematology analyzer IDEXX QBC®, using the procedure specifically proposed for this animal species. Differential leucocyte counts were also done from blood smears prepared from each sample. Mean values of all the parameters evaluated were within the normal limits, reported in the literature.

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Memon, Abdul Salam, Mujeeb Rehman, Aijaz Ahmed Shaikh, and Akmal Jamal. "DEEP VENOUS THROMBOSIS." Professional Medical Journal 23, no. 01 (January 10, 2016): 020–24. http://dx.doi.org/10.29309/tpmj/2016.23.01.757.

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Objectives: To study mean platelet volume (MPV) in deep venous thrombosis(DVT) as evaluated by D-Dimmer and Doppler sonography. Study Design: Case control study.Place and Duration: Department of Surgery, Liaquat University of Medical and Health SciencesJamshoro/Hyderabad from May 2013 to April 2014. Subjects and Methods: A sampleof 106 subjects; 50 controls and 53 diagnosed patients of DVT were studied. DVT patientswere included according to inclusion and exclusion criteria and after results of Sonographyand D-Dimer were available. The Blood samples were collected in bottles containing sodiumcitrate as anticoagulant. MPV was generated by Sysmex KX 21 hematology analyzer. Informedconsent was sought from the volunteer subjects. The Data was analyzed using SPSS version21.0. Statistically significance was defined at p-value of ≤0.05. Results: Mean plateletvolume was elevated in deep venous thrombosis patients which were confirmed by clinicalexamination, sonography and D-Dimer. MPV was elevated in cases; 10.0±0.7fl compared tocontrols; 9.55±0.63fl (p=0.001). D-Dimmer was elevated in deep venous thrombosis patients(p=0.0001). Age, gender and platelet counts did not revealed any significant differencesbetween cases and controls (p>0.0.05). Conclusion: The present study reports elevatedMPV in patients suffering from deep venous thrombosis and it is concluded that MPV may beconsidered as a risk factor for DVT

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Fareed, D., O. Iqbal, M. Tobu, D. A. Hoppensteadt та J. Fareed. "Blood Levels of Nitric Oxide, C-Reactive Protein, and Tumor Necrosis Factor-α Are Upregulated in Patients with Malignancy-Associated Hypercoagulable State: Pathophysiologic Implications". Clinical and Applied Thrombosis/Hemostasis 10, № 4 (жовтень 2004): 357–64. http://dx.doi.org/10.1177/107602960401000408.

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Endogenous generation of nitric oxide (NO) plays an important role in the regulation of cardiovascular and inflammatory responses. This mediator is synthesized by a family of enzymes collectively known as NO synthase. Several isoforms of this enzyme have been identified and can be grouped as constitutive or inducible. Increased production of NO is reported in several inflammatory disorders, such as sepsis, arthritis, thrombotic thrombocytopenic purpura (TTP), and antiphospholipid syndrome. In addition, NO upregulates cyclo-oxygenase-2 and synthesis of several other inflammatory cytokines. Inflammation and thrombotic complications are usually associated with malignancy. Earlier reports indicate the upregulation of tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), and tissue factor (TF) in patients with malignancy. To determine the relationship between inflammatory cytokines and NO in cancer patients with hypercoagulable states, baseline plasma samples from 160 patients with confirmed malignancy and hypercoagulable state were analyzed for NO levels. A chemical method based on a chemiluminescent reaction between NO and ozone using a highly sensitive gas phase NO analyzer was used. CRP, TF, and TNF-α were measured using enzyme-linked immunosorbent assay methods. Of the 160 patients who were plasma tested, the baseline NO levels ranged from 13.7 to 98.6 μM (63.1±15.9 μM, mean±SD) in contrast to age-matched control, which ranged from 9.1 to 34.6 μM (19.8±6.2 μM, mean±SD, n=138). Cancer patients also showed marked variations in the NO levels. Eighteen of 60 cancer patients exhibited greater than 60 μM NO levels. The CRP, TNF-α and TF were also significantly elevated. A correlation between CRP (r2=0.73) and NO levels was noted in cancer patients with hypercoagulable state. These data suggest that the pathogenesis associated with malignancy/hypercoagulable state is associated with an inflammatory component. In addition, the observed hemodynamic changes in some of the cancer patients may be due to increased NO production.

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Choi, Hyun-Woo, Hye-Ran Kim, Hwan-Young Kim, Ju-Heon Park, Jae-Sook Ahn, Duck Cho, Seung-Jung Kee, et al. "Prevalence and Clinical Impacts Of SETBP1 Mutation In East Asian Patients With MDS/MPN." Blood 122, no. 21 (November 15, 2013): 2629. http://dx.doi.org/10.1182/blood.v122.21.2629.2629.

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Abstract Introduction Recently, recurrent somatic SET-binding protein 1 (SETBP1) mutations were found in atypical chronic myeloid leukemia (aCML) and other related myeloid neoplasms. According to reports so far, SETBP1 mutations occur in 9% of myelodysplastic/myeloproliferative neoplasms (MDS/MPN), especially in high frequency (24∼30%) of aCML. SETBP1 mutations were associated with worse prognosis and higher white blood cell (WBC) counts. Most of the reports came from western countries and there was a need to further study its clinicopathological impacts in East Asian patients because of paucity of reports. Therefore, this study investigated the prevalence and clinical implications of SETBP1 mutations in MDS/MPN patients at a single medical center in South Korea. Patients and methods We analyzed a cohort of 34 MDS/MPN patients (10 aCML, 7 CMML-1, 9 CMML-2, 5 JMML, 3 MDS/MPN unclassifiable) who were diagnosed and treated in Chonnam National University Hwasun Hospital (Hwasun, Korea) from October 2004 to June 2013. The mononuclear cells from bone marrow of the patients were separated and the total DNA was extracted by commercial kit (QIAGEN, Hilden, Germany). PCR and sequencing reaction were performed by targeting the hot spot (exon 4, codon 778-979) of the SETBP1 gene. The PCR mixture consisted of 50 to 100 ng of total DNA, 20 pmol of each forward (5'-CCACTTTCAACACAGTTAGGTG-3') and reverse (5'-TCTCGTGGTAGAAGGTGTAACTC-3') primer, 0.4 mM of each dNTP, 5 μL 10X F-taq reaction buffer, 5 U of DNA Polymerase (Solgent, Daejeon, Korea) and H2O in a final reaction volume of 50 μL. Direct sequencing was performed using the ABI Prism 3130XL Genetic Analyzer with the BigDye Terminator v3.1 Ready Reaction Kit (Applied Biosystems). Clinical information about patients was obtained from our electronic medical record database. All statistical computations were performed using PASW 18.0 (SPSS Inc., Chicago, Illinois, USA). Results In this analysis, 4 (11.7%) of 34 MDS/MPN patients showed SETBP1 mutations. 3 of them were aCML patients and 1 was CMML-2 patient. The frequencies in aCML and CMML-2 were 30% and 11.1%, respectively. All of the aCML patients with SETBP1 mutation showed mutation encoding c.2898G>A (p.Asp868Asn) and the CMML-2 patient displayed c.2903C>T synonymous mutation (Ser869).The mutated SETBP1 patients showed a tendency of higher mean WBC counts, lower mean hemoglobin, lower mean platelet counts and lower mean BM blasts percentage than the wild-type patients, but they were not statistically significant. One of the mutated SETBP1 patients showed a i(17)(q10) cytogenetic abnormality. We found no statistical difference in overall survival (OS) between mutated SETBP1 patients and wild-type patients. Conclusions Alteration of SETBP1 gene was a common genetic event in aCML with an impact as a diagnostic marker for MDS/MPN. Disclosures: No relevant conflicts of interest to declare.

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Saouli, Zoi, Georgia Kaiafa, Fotios Girtovitis, Zisis Kontoninas, George Ntaios, George Charisopoulos, Vasiliki Tsavdaridou, Christina Aggouridaki, and Athanasios Papadopoulos. "Correlation of Red Blood Cells and Platelets Parameters." Blood 110, no. 11 (November 16, 2007): 3764. http://dx.doi.org/10.1182/blood.v110.11.3764.3764.

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Abstract INTRODUCTION: Platelet along with red blood cell count is a part of complete blood cell count, one of the most frequent laboratory tests in medicine. Platelet distribution width, plateletcrit and mean platelet volume are three indices provided by hematological analyzers. There are few reports in literature regarding the correlation of these three parameters with red blood cell parameters. AIM: Aim of this study is to investigate the correlation between these platelets parameters and red cell parameters: hematocrit, mean corpuscular volume and red blood cell distribution width. METHODS: Three hundred and three healthy blood donor volunteers (176 men and 127 women, mean age 37,3 years) were included. None of them had any known hematological disease in the past. The parameters mentioned above were measured by the automated hematological analyzer Coulter®LH780. RESULTS: The mean values for platelets were: PCT: 0,25±0,11%, MPV: 8,11±1,94 fL and PDW: 15,89±2,74%. The mean values for their parallel red blood cell parameters were: HCT: 40,55±2,63%), MCV: 91±4,17 fL, RDW: 13,3±1,35% Statistical and regression analysis including the correlation coefficient between platelet and red cell parameters as well as Student’s t-test was carried out. CONCLUSIONS: There seems to be no significant correlation between HCT and PCT. MCV and MPV were not correlated significantly as well, indicating that red blood cell and platelet sizes are independent. But there is a statistically significant correlation between RDW and PDW (r: 0,68, p<0,01) demostrating that anisocytosis of red blood cells and platelets might occur simultaneously. Based on these observations, further more studies should be carried out for the correlation between platelets and red blood cell indices in certain disorders.

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Novis, David A., Molly Walsh, David Wilkinson, Mary St. Louis, and Jonathon Ben-Ezra. "Laboratory Productivity and the Rate of Manual Peripheral Blood Smear Review: A College of American Pathologists Q-Probes Study of 95 141 Complete Blood Count Determinations Performed in 263 Institutions." Archives of Pathology & Laboratory Medicine 130, no. 5 (May 1, 2006): 596–601. http://dx.doi.org/10.5858/2006-130-596-lpatro.

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Abstract Context.—Automated laboratory hematology analyzers are capable of performing differential counts on peripheral blood smears with greater precision and more accurate detection of distributional and morphologic abnormalities than those performed by manual examinations of blood smears. Manual determinations of blood morphology and leukocyte differential counts are time-consuming, expensive, and may not always be necessary. The frequency with which hematology laboratory workers perform manual screens despite the availability of labor-saving features of automated analyzers is unknown. Objective.—To determine the normative rates with which manual peripheral blood smears were performed in clinical laboratories, to examine laboratory practices associated with higher or lower manual review rates, and to measure the effects of manual smear review on the efficiency of generating complete blood count (CBC) determinations. Design.—From each of 3 traditional shifts per day, participants were asked to select serially, 10 automated CBC specimens, and to indicate whether manual scans and/or reviews with complete differential counts were performed on blood smears prepared from those specimens. Sampling continued until a total of 60 peripheral smears were reviewed manually. For each specimen on which a manual review was performed, participants indicated the patient's age, hemoglobin value, white blood cell count, platelet count, and the primary reason why the manual review was performed. Participants also submitted data concerning their institutions' demographic profiles and their laboratories' staffing, work volume, and practices regarding CBC determinations. The rates of manual reviews and estimations of efficiency in performing CBC determinations were obtained from the data. Setting.—A total of 263 hospitals and independent laboratories, predominantly located in the United States, participating in the College of American Pathologists Q-Probes Program. Results.—There were 95 141 CBC determinations examined in this study; participants reviewed 15 423 (16.2%) peripheral blood smears manually. In the median institution (50th percentile), manual reviews of peripheral smears were performed on 26.7% of specimens. Manual differential count review rates were inversely associated with the magnitude of platelet counts that were required by laboratory policy to trigger smear reviews and with the efficiency of generating CBC reports. Lower manual differential count review rates were associated with laboratory policies that allowed manual reviews solely on the basis of abnormal automated red cell parameters and that precluded performing repeat manual reviews within designated time intervals. The manual scan rate elevated with increased number of hospital beds. In more than one third (35.7%) of the peripheral smears reviewed manually, participants claimed to have learned additional information beyond what was available on automated hematology analyzer printouts alone. Conclusion.—By adopting certain laboratory practices, it may be possible to reduce the rates of manual reviews of peripheral blood smears and increase the efficiency of generating CBC results.

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Mazhar, Neelam, Sarah Rafi, Saima Farhan, Shazia Yaseen, and Nisar Ahmed. "Normal Reference Values of Complete Blood Count in Healthy Adult Population of Pakistan; A Multicentre Study." Pakistan Journal of Medical and Health Sciences 15, no. 11 (November 30, 2021): 3040–42. http://dx.doi.org/10.53350/pjmhs2115113040.

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Aim: To establish the reference values of hematological parameters in blood donors of all the four provinces of Pakistan as a general population. Methods: This was a multicenter cross-sectional study conducted from Jan 2017-Oct 2017 in the blood bank and the Dept. of Haematology, The CH&ICH, Lahore, Fatimid Foundation, Karachi, Bolan medical college, Quetta, Armed Forces Institute of Transfusion, Rawalpindi & Ayub medical college, Abbottabad, KPK. Blood samples of 1060 male and female blood donors were collected from the blood banks of all the centers mentioned above. CBC and differential were performed using an automated hematology analyzer in the respective departments. Results: The mean and 95% reference values (2.5th-97.5th) for males WBC 7.752+4.506×109 cells/L, RBC 4.958 +1.331, HB 14.258 +3.423 g/dl, HCT 41.967 +16.345, MCV 84.584 +15.933, PLT 219.485 +197.331, LYM 3.346 +10.112, NEUT 6.843+23.557, MONO 0.811 +3.601, EO 0.327 +0.995. For females WBC 7.174+3.037, RBC4.567 +1.086, HB 12.972 +2.752, HCT39.647 +48.186, PLT 264.07+175.079, LYM 2.537+5.005, NEUT 4.769+11.314, MONO 0.460 +0.909, EO 0.188+0.39 Conclusion: The hematological profile of the population in all four provinces of Pakistan differed from the reports of other countries and the standard reference ranges described in the textbook. So, our own hematological parameters must be followed. More studies must be carried out on other age groups and even on adults to strengthen our results. Keywords: Normal reference values, Complete blood count, Healthy adults of Pakistan

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Koiso, Hiromi, Masamitsu Karasawa, Arito Yamane, Takeki Mitsui, Takafumi Matsushima, Norifumi Tsukamoto, Hirokazu Murakami, Syuichi Miyawaki, and Yoshihisa NOjima. "Prognostic Impact of VH Gene Mutational Status and CD38 Expression in Japanese CLL Patients." Blood 104, no. 11 (November 16, 2004): 4783. http://dx.doi.org/10.1182/blood.v104.11.4783.4783.

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Abstract In the western countries, it has been well established that both immunoglobulin VH gene mutational status and CD38 expression are useful prognostic markers in chronic lymphocytic leukemia (CLL). However, it is not clear whether it is also true in other regions, especially such as Japan where CLL incidence is not so frequent as other countries. Therefore, we investigated the prognostic impact of VH gene mutational status and CD38 expression in Japanese B-CLL. The subjects of this study were 44 patients (29 males and 15 females) referred to our institutions between March 1999 and March 2004. The median age at the time of diagnosis was 68 years (37–92 years). The diagnosis was based on immunophenotypic analysis and cell morphology analyzed on Wright’s–stained peripheral blood and bone marrow smears. Median follow-up period of these patients was 4.0 years (0.5–34.2 years). cDNA mainly prepared from peripheral blood samples of the CLL patients was amplified using VH family-specific framework region primers or leader primers, and CH primers. PCR products were sequenced directly or after TA-cloning using the BigDye Terminator Cycle Sequencing FS Ready Reaction kit on a 310 Genetic Analyzer. Nucleotide sequences were compared to the nearest germ line VH genes in databases: IMGT, V-QUEST or IgBLAST. Of 44 B-CLL patients, IgH variable region genes could be sequenced from their cDNA in 43 patients; no amplified band was obtained in 1 patient. The usage of the seven VH gene families in the 43 B-CLL patients were as following: VH 1, 4/43 (9.3%); VH 2, 2/43 (4.6%); VH 3, 23/43 (53.5%); VH 4, 12/43 (27.9%); VH 5, 1/43 (2.3%); VH 6, 1/43 (2.3%); VH 7, 0/43 (0%). Eighteen cases (41.9%) displayed unmutated V H genes, defined as the sequences having more than or equal to 98% homology with nearest germ line gene, and 25 cases (58.1%) showed somatically mutated, defined as less than 98% homology. The proportion of unmutated cases in this study was almost comparable to previous reports, which showed a range of 30% to 50%. It have been uniformly reported that prognostic difference is apparent between unmutated (bad) and mutated (good) groups. Also in this study, the overall survival, defined as the time from diagnosis to death from any cause or to last contact, was significantly shorter for unmutated cases compared to mutated cases estimated by the Kaplan-Meier method as previous reports: predicted 50% survival rate for the unmutated cases was 9.1 years, but that for mutated cases did not reach the median survival. The difference was significant (p=0.029, log-rank test). Cell surface CD38 expression, which has been reported to correlate with a poor prognosis, was analyzed by flow cytometry in all patients. With the cut off level of 30% in CD19+CD5+ lymphocytes, 13 patients (29.5%) were estimated to be CD38 positive and 31 patients (70.5 %) to be negative. There was no significant difference in overall survival between those 2 groups (p=0.519, log-rank test). In conclusion, VH gene mutational status is a strong prognostic indicator whereas CD38 expression is not in our B-CLL cohort.

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Dale, David C., Merideth L. Kelley, Myriam Navarro-De La Vega, Dhruv Parthasarathy, Deepika Bodapati, Louis Virey, Steve Moffatt, and Tanay Tandon. "A Novel Device Suitable for Home Monitoring of White Blood Cell and Neutrophil Counts." Blood 132, Supplement 1 (November 29, 2018): 1103. http://dx.doi.org/10.1182/blood-2018-99-112647.

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Abstract White blood cell counts (WBC) and absolute neutrophil counts (ANC) are well-established predictors of a patient's risk of fever and infections or febrile neutropenia (FN). Currently, patients at risk of FN due to cancer chemotherapy, idiosyncratic drug-reactions or congenital neutrophil disorders are monitored at hospital or clinic laboratories. For many patients, effective and frequent monitoring is difficult due to the time required and costs of repeated laboratory visits. We herein present the first results for a novel device called Athelas One, a miniature point-of-care hematology analyzer suitable for at home monitoring of WBC and ANC. Methods: Athelas One (A1) is a small cylindrical device with a built-in, single head, light microscope. To determine the WBC and ANC, a small drop of blood (~ 3.5 uL) from a finger stick or an anticoagulated blood sample is drawn by capillary action onto a specially designed microfluidic test strip which creates a stained, precisely dimensioned monolayer of blood cells. The slide is then inserted into the device which scans the test strip and reports the WBC and ANC based on an image analysis process (Computer Vision). We compared results for A1 with a standard laboratory counter [Sysmex XE5000 (SX)]. Results: Initially, A1's reproducibility was demonstrated using 43 blood samples with a wide range of known WBCs (i.e., samples with normal counts, leukocytosis, leukopenia, neutropenia, neutrophilia) run on 4 devices using a single lot of test strips. The A1 results were then compared to SX results using the Passing Bablok Regression with Bootstrap method. These results showed strong linearity and comparability between paired anti-coagulated venous blood samples and the blood samples compared to finger prick capillary blood samples collected almost simultaneously. The slope and intercept indicated a linear relationship, with a 95% confidence for interval slope and intercept containing 1 and 0 respectively. (Comparisons: A1 blood to SX blood: WBC, r=0.998, ANC, r=0.989; A1 capillary to SX blood: WBC, r=0.998, ANC, r=0.97). Table 1 and Figure 1 show a summary of the comparisons. In addition to these results, we have tested 18 samples with WBC < 1.0 x 109/L with closely comparable results for A1 and standard hospital counter. Summary: These initial results show that the WBC and ANC can be accurately determined with a finger stick drop of blood and this point-of-care hematology analyzer. Given its small size, ease of use and accuracy, the device is suitable for home monitoring. Disclosures Dale: Athelas, Inc.: Equity Ownership; Amgen: Consultancy, Research Funding; Sanofi-Aventi: Consultancy, Honoraria; Cellerant: Other: Scientific Advisory Board; Hospira: Consultancy; Prolong: Consultancy; Beheringer-Ingelheim: Consultancy; Coherus: Consultancy. Navarro-De La Vega:Athelas, Inc.: Employment. Parthasarathy:Athelas, Inc.: Employment, Equity Ownership. Bodapati:Athelas, Inc.: Employment, Equity Ownership, Patents & Royalties: patent owned by Athelas on the Athelas One device. Virey:Athelas, Inc.: Employment, Equity Ownership, Patents & Royalties: patent owned by Athelas on the Athelas One device. Moffatt:Athelas, Inc.: Employment, Equity Ownership, Patents & Royalties: patent owned by Athelas on the Athelas One device. Tandon:Athelas, Inc.: Employment, Equity Ownership, Patents & Royalties: patent owned by Athelas on the Athelas One device.

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Pallivilla, Uma Rani, Vahini Gudeli, Maadhurika Ledalla, and Rajendra Jalagam. "Patterns of Neonatal Thrombocytopenia with A Note on Platelet Indices and Optical Technology – A Cross-Sectional Study." Annals of Pathology and Laboratory Medicine 9, no. 7 (August 12, 2022): A148–154. http://dx.doi.org/10.21276/apalm.3177.

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Introduction: Neonatal thrombocytopenia is defined as a platelet count <150×10^9/L regardless of gestational-age. It results from hypo-proliferation in marrow or peripheral destruction of platelets. Platelet count can be rapidly measured using automated hematology analyzers, but peripheral smear remains best method. The causes of neonatal thrombocytopenia are defined by time of presentation into foetal (mainly TORCH infections), early (< 3 days), and late. The present study highlights pattern and severity of neonatal thrombocytopenia in study hospital, adding importance of platelet indices and optical technology. Aim: To study patterns and severity of neonatal thrombocytopenia, platelet indices and to measure accuracy of platelet count by optical technology methods against peripheral smear. Materials and methods: A cross-sectional study done for a period of 8 months from December 2018 to July 2019, at ASRAM medical college, Eluru. During this period blood samples of 113 critical cases of newborns, admitted with thrombocytopenia, were collected in Ethylenediamine tetra acetic acid (EDTA) vials. The platelet count was analyzed by two automated analyzers, Sysmex XN1000 and Horiba ABX Pentra XL 80. The Leishman-stained films were examined under a light microscope. ANOVA test was used to find mean difference between platelet counts, sensitivity, and specificity, and accuracy was calculated by MEDCALC CALCULATOR. Results: Out of total of 113 critical cases of new-borns admitted to Neonatal intensive care unit (NICU) at institute, 85 presented with thrombocytopenia. The variation of platelet indices was noted in 40 cases, blood cultures were collected in 77 cases. Thrombocytopenia showing platelet count less than 20,000/ mm3 is considered very severe, with 30.5% (26 cases) of total number. Elevated platelet indices were noted at 47.5%. The common clinical diagnosis was neonatal sepsis (42.3%), followed by neonatal jaundice (18.8%). The light scatterer principle of platelet evaluation proved to have better accuracy than electrical impedance, in comparison to peripheral smear findings. Conclusion: The study concludes that neonatal septicemia is major cause of neonatal thrombocytopenia as proved by correlating platelet count with platelet indices. And also, usage of automated hemogram reports with platelet indices, is a source of information to suspect etiology of thrombocytopenia thereby preventing adverse outcomes. The principle of Optical Light scatterer technique in an automated analyzer gives better results than the electrical impedance technique for detecting platelet count value, though peripheral smear examination is mandatory for confirmation.

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Bryan, Justin, Christopher Austin, Colleen Thomas, Robert E. Safford, Dong Chen, and Joseph Blackshear. "VWF Multimer Quantitation for Assessment of Cardiac Lesion Severity and Bleeding Risk." Blood 128, no. 22 (December 2, 2016): 2588. http://dx.doi.org/10.1182/blood.v128.22.2588.2588.

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Abstract Introduction: Recent reports have utilized von Willebrand factor (VWF) multimerquantitation in the assessment of native cardiac lesions and prosthetic valve dysfunction. However there is no standardized method for quantitation. We compared 3 methods of assessment which utilized a normal plasma control. Methods: We analyzed 476 samples and their control plasma from 395 patients including normal subjects, patients with aortic stenosis, hypertrophic cardiomyopathy, mitral or aortic regurgitation, normal and abnormal left cardiac valve prostheses, and left ventricular assist device therapy (LVAD). VWF multimers were assessed as normal or abnormal, or as normalized (patient / normal plasma) VWF multimerratios of gel bands >15/2-15 (NMR 15) or gel bands > 10/2-10 (NMR 10). We tested whether one technique was more strongly associated with hemodynamic severity of the cardiac lesion, with a history of acquired bleeding, and compared the results to a separate test of VWF function, platelet function analyzer 15 00 (PFA). Results: Two hundred seventeen patient samples reflected normal or mildly abnormal hemodynamics, 111 moderate, and 113 severely abnormal hemodynamics. Abnormal multimers were present in only 19% of samples with normal or mildly abnormal hemodynamics compared to 79% abnormal in the presence of moderate to severe hemodynamic abnormality. The distinction between moderate and severe hemodynamic abnormality was less striking, 65% versus 88% (figure, left). Quantitative NMR values declined with increasing cardiac lesion severity (figure, middle). The two quantitative multimermethods showed similar relationships to lesion severity by ANOVA, r=0.40 (NMR 15) versus r=0.36 (NMR 10), and by Spearman correlation, r=0.68 for NMR 15, and r=0.66 for NMR 10, and PFA results were comparable (all p< 0.001). Bleeding rates were associated with NMR 15, 10 and PFA (Mann-Whitney p<0.001, figure, right). Conclusion: The dichotomous normal / abnormal VWF multimer method appears to distinguish ≥ moderate hemodynamic disruption, whereas there is a continuous relationship between hemodynamic severity and quantitative multimer methods, which may be clinically useful in circumstances in which clinical estimation of lesion severity is challenging, such as with dysfunctional prosthetic valves. Progressive loss of VWF multimersappears to be associated with bleeding, suggesting that quantitative measures may provide incremental value over the dichotomous normal / abnormal designation. Figure Figure. Disclosures Blackshear: Baxalta, Inc: Consultancy, Research Funding.

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Bidot, Loreta, Wenche Jy, Lawrence L. Horstman, Carlos Jr Bidot, Vincenzo Fontana, Joaquin J. Jimenez, Carlos J. Bidot, and Yeon-Soong Ahn. "Surface Adhesion and Growth of Microaggregates under Flow Condition (II): Clinical Findings in Patients with Thrombosis and Thrombocytopenia." Blood 110, no. 11 (November 16, 2007): 3628. http://dx.doi.org/10.1182/blood.v110.11.3628.3628.

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Abstract BACKGROUND. Ideally, thrombophilic states should be evaluated under in vitro conditions as close as possible to in vivo. We have been evaluating cell adhesion to surface and subsequent growth of microaggregates employing a new instrument intended to approach that ideal. We utilized the Diamed Impact-R, in which whole blood is added to a cone-and-plate analyzer (CPA) equipped with an image analyzer, and the resulting microaggregates adhering to the plastic plate after shearing are measured by three parameters: number of object adhering, average size of aggregate, and percent surface coverage (SC) by aggregates. (A companion abstract reports in vitro findings indetifying variables affecting results.) METHODS: Blood was drawn in citrate Vacutainers and 130 uL was applied to the instrument ≤3hr after drawing. The CPA was operated at shear rate 1800 sec−1 with 2min run time. Subjects were also assayed for cell-derived microparticles (MP) from leukocytes (LMP, CD45+), platelets (PMP, CD41+), red cells (RMP, glycophorin+) and endothelium (EMP, CD62E+ or CD31+/CD41−) by flow cytometry. MP which bound FITC-annexin V (AnV) were also measured. We investigated normal healthy controls and 2 groups of patients. Subjects consisted of n=33 normal controls (NC); n=38 with recent thrombosis (TBS) but stable for at least 4 wk, of various subgroups (DVT, APS, TIA, MI); n=35 patients with thrombocytopenia (TP, mostly ITP). RESULTS: In NC, the means ±SD for SC, size, and number of aggregates were 10.3±2.5%, 41.4±14.1 um2, and 1540±381, respectively. In patients with TBS, SC and size were significantly higher (SC: 13.0±3.1%, p=0.0002; size: 54.5±22.9 um2, p=0.006) compared to NC. Interestingly, however, there was no difference in number of aggregates between these groups. In patients with TP, SC and number were significantly lower (SC, 6.3±4.0%, p=0.0001; number, 793±417, p=0.00001) than NC, but there was no difference in size of aggregates. When TBS vs. TP groups were compared, all 3 parameters were higher in TBS (SC, p=0.000001; size, p=0.02; number, p=0.000001). To gauge if the method might be useful clinically, we determined how many patients departed from the NC mean by ≥2SD: best was parameter SC, for which 11/38 (29%) TBS were >2 SD above the mean. On the other hand, 18/35 (51%) TP were >2SD below the mean. We attribute this moderate degree of sensitivity to the large SD (high variability) of the NC group. Lastly, we found that AnV+ MP correlated strongly with parameter SC (R=0.65, p<0.0001), as did EMPCD31+ (R=0.60, p<0.001). The other MP measured did not correlate convincingly with SC, size or number. CONCLUSIONS: Our studies show that in thrombotic patients, parameters SC and size of aggregates but not number of objects were significantly elevated compared to NC. The underlying mechanism of this effect is currently unknown. Our data suggest that cell-derived microparticles, specifically AnV+ MP or EMP, may be involved with increased surface coverage and aggregate size. On the other hand, in TP patients, we observed a lower surface coverage and number of objects. This appears to be due to lower platelet counts. These tests appear promising for evaluating thrombophilic or thrombocytopenic states. However it is required to reduce the high variability by evaluating variables such as shear rate, run time, surface coating, platelet and MP count.

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Pitti, Pauline, Françoise Tassin, and Aurore Keutgens. "Contribution of hematology analyzers (Sysmex XN-Series) in the rapid diagnosis of malaria: case reports." Annales de Biologie Clinique 00, no. 00 (March 2023): 00. http://dx.doi.org/10.1684/abc.2023.1791.

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Koren-Michowitz, Maya, Hagit Hauschner, Yulia Shuly, Meital Nagar, Elena Ribakovsky, Mudi Misgav, Odit Gutwein, Uri Seligsohn, Nurit Rosenberg, and Arnon Nagler. "Essential Thrombocythemia Patients with CALR Mutations Have Increased Platelet Activation Markers Compared to JAK2V617F Mutated Patients." Blood 124, no. 21 (December 6, 2014): 3223. http://dx.doi.org/10.1182/blood.v124.21.3223.3223.

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Abstract Essential thrombocythemia (ET) is associated with an increased risk for thrombo-hemorrhagic complications. The presence of the JAK2V617F mutation, found in approximately 50% of ET patients, has been associated with increased indices of platelet (PLT) activation suggesting its casual role in thrombus formation. Mutations in CALR were recently described in the majority of JAK2V617F negative ET patients, and are associated with a decreased rate of thrombotic events. This has led us to hypothesize that CALR mutations have a different influence on PLT activation compared to JAK2V617F. To evaluate the PLT activation state, surface expression of two PLT activation markers - p-selectin (CD62P) and PAC1 was studied using specific antibodies. MFI was analyzed by flow cytometry at baseline, as well as following ADP addition to PLT rich plasma. Monocyte-platelet aggregates were studied in whole blood samples by gating CD45+/CD14+ cells and calculating the percentage of CD41+ cells in the monocytes population. The immature PLT fraction (IPF) was analyzed with the XE-5000 hematology analyzer (Sysmex UK Ltd., Milton Keynes, UK), and the absolute number of immature PLT (nIP) was calculated from the total PLT count. Low risk ET patients (N-13, M/F-5/8) and healthy controls (N-10, M/F-4/6) are included in this analysis. JAK2V617F and CALR mutations were present in 8 and 5 patients, respectively; low dose aspirin (range 75-100mg) was taken by 85% of patients and 90% of controls. Median PLT count in CALR mutated, JAK2V617F mutated and healthy subjects was 913, 579 and 247 K/uL, respectively (p=0.0002), and it was higher in CALR compared to JAK2V617F positive patients (p=0.09). Both patient subgroups had a lower baseline MFI of p-selectin and PAC1 compared to healthy controls (p-selectin: 2.8, 3 and 4.5 for JAK2V617F [p=0.01], CALR [p=0.05] and controls; PAC1: 3, 3.3 and 5.2 for JAK2V617F [p=0.01], CALR [p=0.02] and controls, respectively) with no difference between CALR and JAK2V617F mutated patients. CALR compared to JAK2V617F mutated patients had higher median number of immature PLT (30 and 10.6 K/uL, p=0.04), and a higher fraction of monocyte- platelet aggregates (90 and 58%, p=0.05). nIP and monocyte- platelet aggregates were also significantly higher in CALR mutated but not in JAK2V617F mutated patients compared to healthy controls. Interestingly, there was no difference in post ADP PLT activation (post/baseline ratio) between ET patients and healthy controls. Finally, there were correlations between the PLT counts and nIP (R=0.8, p<0.0001), monocyte- platelet aggregates (R=0.5, p=0.02), baseline p-selectin MFI (R=-0.5, p=0.02) and PAC1 MFI (R=-0.5, p=0.01). Our preliminary results suggest a correlation between PLT activation markers and the PLT numbers, which can explain why CALR mutated patients in our cohort had higher nIP and monocyte- platelet aggregates fractions. The absence of an increased ADP induced PLT activation between patients and controls in this cohort compared with previous reports could be explained by the use of aspirin in the majority of patients and the high ADP concentration used for PLT activation. These results will be further studied in a lager cohort of patients. Disclosures No relevant conflicts of interest to declare.

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Park, Seo-Jin, Hyun-Sook Chi, Kyung Ran Jun, Sook Kyoung Min, Seongsoo Jang, Chan-Jeoung Park, Kyoo Hyung Lee, Je-Hwan Lee, Jung-Hee Lee, and Dae-Young Kim. "Rapid Detection of Nucleophosmin (NPM1) Mutations to Determine Prognostic Implications in Acute Myeloid Leukemia Patients with a Normal Karyotype." Blood 114, no. 22 (November 20, 2009): 4676. http://dx.doi.org/10.1182/blood.v114.22.4676.4676.

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Abstract Abstract 4676 INTRODUCTION Mutations of the nucleophosmin gene (NPM1) occur in up to 40-50% of adult acute myeloid leukemia (AML) with a normal karyotype and are associated with a higher frequency of fms-like tyrosine kinase-3 internal tandem duplications (FLT3-ITD) and responsiveness to induction chemotherapy. The incidence of NPM1 mutations in Caucasians have been previously reported in several studies whereas there have been few reports from Asian countries including Japan, China, and Taiwan. The objectives of our study was to determine the prevalence of NPM1 mutations and distribution of AML subtypes in the normal karyotype AML Korean population in addition to establishing an easily applicable yet reliable method to indentify these mutations. We also examined treatment outcomes and survival (relapse-free survival (RFS) and overall survival (OS)) by stratifying them into groups according to NPM1 and FLT3-ITD mutation status. METHODS We retrospectively analyzed the prevalence of NPM1 mutations in 185 patients with normal karyotype AML diagnosed between 2002 and 2009. Genomic DNA extracted from bone marrow aspirate specimens obtained at diagnosis was amplified by PCR, followed by analysis on an ABI 3130 Genetic Analyzer (Applied Biosystems) by capillary electrophoresis. Cases found to have mutation peaks at 174bp by Gene Mapper ID v3.2 software (Applied Biosystems) were further analyzed by direct sequencing of exon 12 of NPM1 gene. Follow-up data was reviewed by retrospective chart review for treatment outcome and survival analyses. Among the 185 AML patients, 18 with less than a 1-month follow-up period were excluded since they could not be sufficiently evaluated. RESULTS Mutations in exon 12 of NPM1 were found in 37 of 185 (20.0%) normal karyotype AML patients and were composed of TCTG duplications (Type A, 32/37, 86.5%), 3 previously reported variants, and 2 new variants previously not reported. Mutations were most frequently seen in AML M1 patients (12/37, 32.4%) and other subtypes such as M2, and M4 were often observed. NPM1 mutations were particularly associated with CD34-negativity (<0.0001) and higher bone marrow blast (%) at diagnosis (p=0.0067). There was a mild trend towards frequent FLT3-ITD mutations in NPM1+ patients in comparison to the NPM1- group (35.1% and 19.6%, p=0.0787). After exclusion of the 18 patients lost during follow-up, no significant differences in RFS (8.5 and 10.8 months, p=0.7922) and OS (11.5 and 13.6 months, p=0.6147) were observed between the NPM1+ and NPM1- groups. Stratification into good (NPM1+/FLT3-ITD-), intermediate (NPM1-/FLT3-ITD- & NPM1+/FLT3-ITD+), and poor (NPM1-/FLT3-ITD+) prognostic groups did not reveal significant differences in median values of RFS and OS (in months; RFS, 16.0 and 13.8 and 7.3, p=0.1872; OS, 16.0 and 10.8 and 7.3, p=0.3661). However, the Kaplan-Meier survival analysis of these stratified prognostic groups showed a trend toward a difference in RFS (p=0.084) and a significantly longer OS in the NPM1+/FLT3-ITD- (good prognostic) group (p=0.031). CONCLUSIONS The prevalence of NPM1 mutations in normal karyotype AML patients in Koreans was lower than those reported in Western studies. In areas with low prevalence, a screening method to detect mutations enables rapid reporting with only selective cases requiring the labor-intensive direct sequencing step. In accordance with previous studies, a significantly longer OS in the NPM1+/FLT3-ITD- group suggests that NPM1+ may be associated with a favorable outcome. However, discordant parameters such as prevalence and RFS may signify that elucidation of the prognostic significance of NPM1 mutations in different ethnic groups may be necessary. Thus, NPM1 mutation studies should be considered in the diagnostic work-up of all AML patients with a normal karyotype given its role as a prognostic marker. Disclosures: No relevant conflicts of interest to declare.

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Mitsiades, Constantine S., Nicholas Mitsiades, Galinos Fanourakis, Athina Goudopoulou, Ciaran J. McMullan, Gerasimos Voutsinas, Nikhil C. Munshi, and Kenneth C. Anderson. "Evaluation of the Ras/B-Raf/SHP-2 Axis in B Cell Malignancies." Blood 104, no. 11 (November 16, 2004): 4344. http://dx.doi.org/10.1182/blood.v104.11.4344.4344.

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Abstract The Ras/Raf/MEK/MAPK pathway is a major regulator of tumor cell proliferation. Ras mutations have been known in many malignancies for several years, whereas more recent reports have shown that activating mutations of the BRAF gene are present in a large percentage of human malignant melanomas and thyroid carcinomas and in a substantial proportion of colon carcinomas (Nature2002;417:949–54). The vast majority of these mutations represent a T1796A change resulting in a V599E substitution within the activation segment of B-Raf. This mutant B-Raf kinase is constitutively active and results in inappropriate stimulation of downstream MAPK/ERKs and tumor cell proliferation. The PTPN11 gene encodes SHP-2 (Src homology 2 domain-containing protein tyrosine Phosphatase), a nonreceptor tyrosine protein tyrosine phosphatase (PTPase) that modulates Ras signaling. Germline mutations in PTPN11 are responsible for Noonan syndrome (NS), whereas somatic mutations have been detected in juvenile myelomonocytic leukemia (JMML). We investigated the presence of mutations in the Ras/B-Raf/SHP-2 axis in 25 lines from B-cell malignancies, including 19 multiple myeloma (MM) cell lines. DNA was isolated and B-Raf (exons 11 and 15), PTPN11 (3 and 13) and K-, N- and H-Ras sequences were amplified by PCR using specific flanking primers. The PCR products were purified and sequenced in automatic sequencer (ABI PRISM 3100 Genetic Analyzer; Applied Biosystems). Ras gene mutations were found in 11/25 (44%) of the studied cell lines. None of the previously described activating B-Raf mutations, including the most prevalent V599E, were found in our panel. Only one MM cell line demonstrated a C1332A substitution, which corresponds to a D444E change, which is predicted to have a minimal, if any, impact on kinase activity. A single PTPN11 G178C substitution, corresponding to a G60R change (previously described in NS and AML), was detected in another MM line. These data confirm the previously known role of Ras mutations in B-cell malignancies and identify a rare occurrence of a PTPN11 mutation in our panel. On the other hand, activating mutations of the B-Raf kinase are unlikely to play a significant part in the pathogenesis of B cell malignancies, in contrast to their prominent role in several types of solid tumors. In total, our data suggest that the Ras/Raf/MEK/MAPK can be overactive in these malignancies due to activating genetic events upstream of B-Raf, such as the previously described activating Ras mutations.

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Gabriel, Don A., Brett E. Skolnick, Stephanie Seremetis, Philip Leese, and David Mathews. "Effect of Recombinant Activated Factor VII (rFVIIa) on Platelet and Clotting Systems in Healthy Volunteers." Blood 106, no. 11 (November 16, 2005): 4053. http://dx.doi.org/10.1182/blood.v106.11.4053.4053.

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Abstract The generation of thrombin is a critical step in clot formation and securing hemostasis. Inadequate thrombin generation may result in excessive bleeding, while uncontrolled thrombin production has the potential to induce thromboses. Recombinant FVIIa has been shown to control bleeding in hemophilia patients with inhibitors to coagulation factors VIII and IX, and several other clinical conditions in which life- and limb-threatening bleeding may occur. However, for non-hemophilia patients the dose and dosing regimen still require refinement. The use of ex-vivo assessment systems (Thromboelastograph assay, Hemodyne Hemostasis Analyzer) to generate an in vitro model of hemostasis may be useful to determine the effect of rFVIIa on the dynamics of clot formation, particularly in a patient population where clinical trials are difficult. A series of pilot studies were performed to establish an optimal punch biopsy location and biopsy size to create an effective bleeding site for further study. The current study (48 subjects consented for an IRB approved protocol) examined, in an ascending dose-escalation manner, the effect of an individual dose of rFVIIa on bleeding time, blood loss volume, coagulation parameters and coagulation status in healthy volunteers. All patients underwent three punch biopsies: the first (baseline biopsy) with no treatment, the second and third biopsy with either a low or high rFVIIa dose administered prior to biopsy. The treatment pair sequences were placebo/10, 10/20, 20/40, 40/80, 80/120, and 120/160 μg/kg. Blood samples were drawn 15 minutes pre-, 15 minutes post-, 1 hour and 5 hours post-biopsy to conduct ex-vivo assessments of hemostasis. The results indicate that overall there was a trend towards an increase in platelet contractile force and clot elastic modulus with an apparent maximal effect at 1 hour post-biopsy. At the higher doses this effect, although reduced, does not return to pre-treatment values by 5 hours post-biopsy. For the lower doses these values decreased to levels comparable to those at pre-treatment. These observations are consistent with the reports of a dose-related half-life of rFVIIa. These data imply that the administration of rFVIIa may have an effect in non-coagulopathic individuals. Although the heterogenity observed in this sample of patients may limit interpretations, it is proposed that this ex-vivo model with further refinements may be useful for evaluating the effects of future pro-hemostatic agents. Figure Figure

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Yassin, Mohamed A., Hanadi Rafii El-Ayoubi, and Nader Al-Dewik. "High Percentage of JAK2 exon 12 Mutation in Polycythemia Vera and Essential Thrombocythemia Among Populations of Qatar." Blood 120, no. 21 (November 16, 2012): 5064. http://dx.doi.org/10.1182/blood.v120.21.5064.5064.

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Abstract Abstract 5064 The chronic myeloproliferative Neoplasm (NPM) are clonal hematopoietic stem cell malignancies with 3 main subtypes: polycythemia vera (PV), essential thrombocytosis, and idiopathic myelofibrosis. PV is characterized by increased RBC proliferation in the absence of erythropoietin and proliferation of myeloid lineages usually is noted, A gain-of-function mutation of Janus kinase 2 (JAK2) V617F, is identified in about 95% of patients with PV and about 50% of patients with essential thrombocytosis and idiopathic myelofibrosis. It has been shown that JAK2 exon 12 mutations can activate erythropoietin signaling pathways while these findings have been confirmed by many studies from Western countries, there are no reports from Asian countries in general and Arab countries in particular about the prevalence of the JAK2 exon 12 mutation in patients with PV and ET. In the present study, we determined the prevalence of JAK2V617F and JAK2 exon 12 mutations in patients with PV and ET in Qatar. Materials and Methods We enrolled patients with a diagnosis of PV and ET at National Centre for Cancer Care and Research in Qatar from January till June 2012. The diagnosis of PV and ET was established according to the 2008 World Health Organization criteria. The study included 82 patients. Clinical information and the CBC data at diagnosis were obtained from medical records. Pretreatment serum erythropoietin levels. Total DNA was isolated from buffy coat cells taken from peripheral blood using a kit (QIAamp DNA Mini Kit, Qiagen, Hilden, Germany) according to the manufacturer's instructions. Allele-specific polymerase chain reaction (PCR) was performed using 80 ng of genomic DNA as the template in a35-cycle PCR reaction at an annealing temperature of 58°C, as previously described. The mutant allele yields a 203-base-pair (bp) PCR product (sensitivity of mutant allele detection <1%). For exon 12 mutation screening, 80 ng of genomic DNA was amplified by specific primers designed to amplify a region of 453 bp containing the 128 bp of the exon 12 sequence of JAK2. PCR products were directly sequenced in both directions on an ABI 3730 DNA Analyzer using the BigDye Terminator Sequencing kit. Results We examined the occurrence of JAK2V617F and JAK2 exon 12 mutations in a clinical cohort of 82 patients with polycythemia vera (PV) and Essential thrombocythemia (ET) Of which 42 patients had PV aged 25 to 53, 13 (31%) females and 29 (69 %) males and V617F mutation was detected in all of them exon 12 mutation was detected in 38 (90. 47%) patients. We found 2 different exon 12 mutations:3 N542-E543del, 1 F537-K539delinsL, and among 40 ET patients aged 25 to 59, 22 (55 %) males and 18 (45%) females, 35 patients (87. 5%) were JAK2 V617F and JAK 2 exon12 positive and 5 (12. 5%) were JAK2V617F as well as exon 12 negative patients with V617F and exon 12 mutations showed significantly higher WBC and platelet counts at diagnosis than patients with exon V617F mutation alone (P =. 021 and P =. 038, respectively). We report a surprisingly high incidence of exon 12 mutations in MPN patients with PVand ET in Qatar, a result quite different from reports in the Western literature (P =. 001). Conclusion Our data suggest that exon 12 mutation of JAK2 in patients with PV and ET may have an uneven geographic distribution. A clinical laboratory providing the V617F test alone may risk missing a substantial number of patients with PV in areas with a high incidence of exon 12 mutation. the importance of such associations may need further studies and evaluations. Disclosures: Yassin: Qatar National Research Fund: Patents & Royalties, Research Funding. Rafii El-Ayoubi:Qatar National Research Fund: Patents & Royalties, Research Funding. Al-Dewik:Qatar National Research Fund: Patents & Royalties, Research Funding.

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Gabriel, Don A., Brett E. Skolnick, Philip Leese, and David Mathews. "Ex-Vivo Assessments in the Evaluation of Dose Response to Recombinant Factor VIIa When Administered for Bleeding Following Punch Biopsies in Healthy Volunteers." Blood 106, no. 11 (November 16, 2005): 4055. http://dx.doi.org/10.1182/blood.v106.11.4055.4055.

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Abstract The utility of existing methods for the evaluation of hemostatic agents has been limited. The purpose of this study was to evaluate and optimize the use of a standardized punch biopsy to investigate the effects of hemostatic agents in healthy subjects. Recombinant FVIIa (rFVIIa) is licensed for the treatment of bleeding episodes in patients with hemophilia A or B with inhibitors. Recent reports (anecdotal and from randomized clinical trials) have described the successful use of rFVIIa in patients with liver disease, intracerebral hemorrhage, congenital and acquired coagulation factor deficiency, warfarin-induced bleeding, thrombocytopenia, traumatic brain injury, spinal cord surgery, and platelet disorders using a wide range of doses and dosing regimens. This variety of clinical situations, suggests a need to determine the optimal dose and dosing regime of rFVIIa for use in these potentially new therapeutic areas. A study was designed to evaluate the dose-response of rFVIIa in a controlled manner using a punch biopsy procedure in healthy volunteers that consented to participate in an IRB approved protocol. The study was designed as a three-part trial. Part A (6 subjects) optimized the size of the biopsy needed to create bleeding times and durations appropriate for study purposes. Part B (10 subjects) determined the feasibility of evaluating rFVIIa efficacy and safety in this bleeding model. Part C (48 subjects) examined, in an ascending dose escalation paradigm, the effect of a single dose of rFVIIa on bleeding time, blood loss volume, coagulation parameters and coagulation status in healthy volunteers. In Part C, all patients underwent three punch biopsies: the first (baseline biopsy) with no treatment, the second with either a low or high rFVIIa dose administered prior to biopsy, the third with either a low or high dose of rFVIIa administered prior to biopsy. The treatment pair sequences were placebo/10, 10/20, 20/40, 40/80, 80/120, and 120/160 μg/kg. Blood samples were drawn 15 minutes pre-, 15 minutes post-, and 1 hour post-biopsy to monitor coagulation and conduct ex-vivo assessments of hemostasis [Hemodyne Hemostasis Analyzer (HHA)]. Safety evaluations were conducted by an Independent Safety Officer after each dose tier, and subjects were permitted to enroll in the next higher dose tier only if no significant safety issues were observed. In healthy subjects with no pre-existing coagulopathies, regression analyses indicated that increasing doses of rFVIIa did not have a dose-related linear effect on blood loss volume or duration of bleeding. However, it is of interest that with HHA, a statistically significant impact was noted on the time to 20 mm clot strength, platelet contractile force, and clot elastic modulus, suggesting that rFVIIa does have a measureable and perhaps meaningful effect in individuals with normal coagulation systems. No safety issues were detected during this study. Thus in this model system, designed to evaluate hemostasis, interesting effects were seen with the HHA instrument which suggest that increasing doses of rFVIIa may impact clot stability, but these observations are limited by the significant hetereogeneity which may benefit from improved experimental controls.

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Tashi, Tsewang, Dottie Hussey, Felipe R. Lorenzo V, Parvaiz Koul, and Josef T. Prchal. "High Altitude Genetic Adaptation In Tibetans Does Not Include Increased Hemoglobin-Oxygen Affinity." Blood 122, no. 21 (November 15, 2013): 937. http://dx.doi.org/10.1182/blood.v122.21.937.937.

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Abstract Increased hemoglobin-oxygen affinity has been shown to be an adaptive response to hypoxia in many high altitude animals such as the Andean goose, guinea pig and llamas (Reynafarje C. 1975; Hebbel R. 1978). It has been reported that people living in a high altitude, hypoxic environment have also developed a similar adaptation. Native Tibetans are known to have lived at an average of 3000-5000 meters on the Tibetan Plateau for more than 20,000 years, and have undergone genetic adaptations that have enabled them to thrive in this reduced oxygen environment. Most Tibetans are thus protected from polycythemia and other features of chronic mountain sickness. Several studies have reported higher arterial oxygen saturations among Tibetans as part of their genetic adaptation (Beall C. 1994; Moore L. 2001; Niermeyer S. 1995), thereby concluding that they have higher hemoglobin-oxygen affinity. Further, recent genomic studies have reported that beta-globin haplotypes (HBB and HBG2) have been selected in Tibetans, suggesting the presence of hemoglobin variants as a beneficial factor of Tibetan adaptation (Yi. 2010). However, some of the reports of increased hemoglobin-oxygen affinity are based on single readings of arterial oxygen measurements. Hemoglobin-oxygen affinity is more optimally measured by deriving the P50 value, which is the partial pressure of oxygen at which hemoglobin is 50% saturated with oxygen. A decreased P50 can be due to mutated globin genes resulting in high oxygen affinity hemoglobins, low 2,3 BPG, high pH or low temperature. The hemoglobin-oxygen dissociation is optimally derived by hemoximeter measurements of the percent saturation of hemoglobin at various partial pressures of oxygen. The resultant curve has a sigmoid shape due to the cooperative binding of oxygen to the four globins in the hemoglobin tetramer; this cooperative interaction can be enumerated as a Hill coefficient “n”. If a hemoximeter is not readily available, the P50 can be estimated from the venous blood gas using the measured pO2, hemoglobin oxygen percent saturation O2%, and pH (Lichtman M. 1976); however the Hill coefficient “n” cannot be derived by this method. To definitely establish whether the Tibetan adaptation to high altitude hypoxia involves increased hemoglobin-oxygen affinity, we conducted the following study of direct and indirect oxygen-hemoglobin affinity among Tibetans living at two different altitudes. We enrolled 14 healthy ethnic Tibetans and one closely related Nepalese Sherpa. There were 8 males and 7 females ages ranging 35-75 years. The first group consisted of 5 ethnic Tibetans living in Srinagar, India (1,600 meters), on whom venous blood gases were done and the P50 was derived using pH, PO2 and O2 saturation using the formula described by Lichtman and colleagues. Three were born in Tibet and two were offspring of Tibet-born parents. The second group consisted of 10 volunteers (9 Tibetans and one Nepalese Sherpa) residing in Salt Lake City, UT, (1,300 meters) whose peripheral blood was evaluated by Hemox Analyzer for obtaining P50 values and “n” Hill coefficients for hemoglobin oxygen binding. All the ethnic Tibetans in Salt Lake City were born in Tibet except for one, and the Nepalese Sherpa was born in Nepal. The results are depicted in Table. The P50 measured by venous blood gases on the Tibetan volunteers from Srinagar, India and those measured by Hemox Analyzer on the 10 volunteers from Salt Lake City, UT were normal, with values in the normal range (22-28 mmHg). No hemoglobin variants were detected by high pressure liquid chromatography in these 15 Tibetan volunteers.TableSubject IDP50 (mmHg)“n” Hill CoefficientS 0526.38n/aS 0825.95S 1326.55S 1523.68S 2722.72U 1926.962.97U 2025.162.83U 2124.202.89U 2225.462.84U 2322.502.89U 2424.062.87U 2524.282.83U 2622.352.82U 2723.292.79U 2825.992.75 We report no evidence for the presence of high hemoglobin-oxygen affinity in Tibetans as a constituent of their genetic adaptation. Our data rule out the existence of hemoglobin variants and aberrant 2,3 BPG metabolism as possible features of Tibetan high-altitude adaptation; however acquired transient metabolic alterations at high altitudes, cannot be excluded to account for possible changes in hemoglobin-oxygen affinity but these are not evolved persistent features of Tibetan genetic adaptation. Studies of Tibetans living in these extreme hypoxic environment (>4,000m) are now planned. Disclosures: No relevant conflicts of interest to declare.

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Carr, Marcus E., Erika J. Martin, Janice G. Kuhn, and Melinda Nolte. "At 90 Micrograms Per Kilogram, Recombinant Factor VIIa Partially Corrects Abnormal Hemostatic Function in Blood from Factor IX Deficient Patients." Blood 104, no. 11 (November 16, 2004): 1044. http://dx.doi.org/10.1182/blood.v104.11.1044.1044.

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Abstract Reports of the potential clinical utility of recombinant Factor VIIa (rFVIIa, NovoSeven®, NovoNordisk) in a variety of bleeding disorders have raised the possibility that this agent may have broad spectrum hemostatic properties. We have previously demonstrated that rFVIIa produces dose dependent correction of hemostatic status in patients with Factor VIII deficiency and/or Factor VIII inhibitor. In this study we measured the dose dependent effects of rFVIIa on Platelet Contractile Force (PCF), Clot Elastic Modulus (CEM) and Thrombin Generation Time (TGT) (Hemodyne® Analyzer, Hemodyne, Inc.) in patients with factor IX deficiency. Results were compared to those seen with recombinant factor IX (BeneFIX® [GI, Wyeth]) and factor nine concentrate (Mononine® [Aventis-Behring]). Blood from three patients with factor IX deficiency was collected via aseptic venipuncture into evacuated tubes containing 3.2% sodium citrate. The samples were spiked with increasing amounts of each hemostatic agent so as to yield levels ranging from 25 to 200% of the recommended dose. At baseline, each of the factor IX deficient patients had prolonged TGT, decreased PCF and decreased CEM. Despite the fact that each patient had less than 1% of normal factor IX activity, there was significant variability between the patients in their baseline values. TGT for the three patients varied from 587 to 1200 seconds. Baseline PCF ranged from 0.9 to 1.4 Kdynes, while CEM varied from 1.6 to 5.4 Kdynes/cm2. Normal TGT, PCF and CEM values for asymptomatic controls (mean ± SD, n=25) were 392±100 seconds, 7.8±1.3 Kdynes and 18.8±5.6 Kdynes/cm2 respectively. At the 100% of recommended dose, each of the factor IX agents produced shortening of the TGT, and increases in PCF and CEM. The degree of normalization of these parameters did not appear to depend on the baseline values. The patient with the worst baseline parameters completely normalized his values at 100% doses of BeneFIX® and Mononine®. The patient with the best baseline values also normalized his parameters with BeneFIX® but not with Mononine®. The patient with intermediate baseline abnormalities improved all parameters with both factor IX products but appeared to respond better to BeneFIX® at the 100% dose level. The response to NovoSeven®, at 100% of the dose recommended for treatment of factor VIII inhibitor patients, was detectable but clearly inferior to the response to the factor IX agents. These results indicate significant variability in hemostatic status between factor IX deficient patients both at baseline and in response to factor replacement. While rFVIIa has activity in these patients, the dose previously shown to correct TGT in factor VIII deficient patients may not be appropriate for factor IX deficient patients.

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Vadasz, Zahava, Tamar Tadmor, Jacob Bejar, and Dina Attias. "Enhanced Apoptosis and Reduced Angiogenesis in DLBCL." Blood 106, no. 11 (November 16, 2005): 4681. http://dx.doi.org/10.1182/blood.v106.11.4681.4681.

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Abstract Introduction: Angiogenesis is a necessary step in tumors progression correlating and beeing indicative of an unfavourable prognosis. Preliminary reports indicated that microvessel quantification may be useful in predicting tumors outcome. There is scant data regarding caspase-3 and vascular endothelial growth factor(VEGF) as well as the appraisal of vessel density in diffuse large B-cell lymphomas (DLBCL). These aforementioned variables are of significance in the surveillance and prognostic assessment of patients diagnosed and treated for DLBCL. The purpose of the abstract is to report our findings concerning the different biological characteristics between follicular lymphoma (FL) and DLBCL regarding angiogenesis and apoptosis. MATERIALS AND METHODS: Nodal biopsies from 40 patients suffered from DLBCL were analysed. Control group included nodal biopsies from FL(5 patients) and benign nodal hyperplasia (5 patients). Microvessel quantification was performed by immunohistochemical staining, using monoclonal antibodies against factor VIII related antigen (F8RA) and against CD34. The assessment of caspase 3 level of expression was done by using monoclonal specific antibody. We also assessed the level of expression of VEGF and Ki-67 (by using specific monoclonal antibodies, qualitatively, was done by two separate trained pathologists). The evaluation of the microvessel density (MVD) and the caspase 3 was done by using the Image analyzer" Provision". Results: All the biopsies that were included had proliferative index between 40–60%. VEGF was expressed in all DLBCL, follicular lymphoma and benign nodal hyperplasia specimens, mainly extracellulary. There was no qualitative difference in the level of VEGF expression in the various biopsies. By using the Provision analysis of the MVD, we demonstrated low level of angiogenesis in nodal DLBCL as opposed to the marked angiogenesis shown in FL and benign nodal hyperplasia. The average MVD in DLBCL specimens was 17±5, in the tumor margins 48±10, FL 55 ±10 and benign nodal hyperplasia 63±5. The morphology of the blood vessels showed diversity: while in the DLBCL the blood vessels were small and almost undeveloped, in the DLBCL tumor margins, in FL and benign nodal hyperplasia the blood vessels are fully developed, large and numerous. We assessed the apoptotic level by using anti caspase 3 antibody. Remarkable difference was demonstrated: the positive caspase-3 expressing DLBCL cells was 60±12, in the FL cells it was 6± 3, and in the benign nodal hyperplasia cells it was 2±2. Discussion: In this preliminary study different biological characteristics were observed in DLBCL as opposed to FL: as in DLBCL there is low angiogenesis and high apoptotic activity, in FL and in benign nodal hyperplasia there are high angiogenic activity and low apoptotic rate. We postulate that the high apoptotic rate in DLBCL may be linked to the low angiogenesis: probably the high rate of the cellular turnover in the tumor does not permit blood vessels formation. On the other hand, the low angiogenic activity in the tumor, may, not allow sufficient nutrients and cytokins supply to the tumor cells and thereby cause to the high apoptotic rate of the tumor cells. Anti angiogenic therapy has been introduced in the last years in hematologic malignancies. Taking into consideration the above preliminary results, it is uncertain that patients suffered from DLBCL will benefit from the anti-angiogenic compounds. Further studies and clinical trials are warranted.

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Nomdedeu, Josep F., Montserrat Hoyos, Maite Carricondo, Elena Bussaglia, Camino Estivill, Jordi Esteve, Mar Tormo, et al. "WT1 Levels At Diagnosis and POST-Induction Provide Prognostic Information in Adult De Novo AML. Results From the Spanish Cetlam Group." Blood 120, no. 21 (November 16, 2012): 2524. http://dx.doi.org/10.1182/blood.v120.21.2524.2524.

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Abstract Abstract 2524 WT1 monitoring is an almost universal target to follow de novo AML. Its exppression in myeloid malignancies is upregulated in parallel to the blast percentage. Recently, WT1 determination has been standardized as result of an European Leukemia Net initiative. Early reports have demonstrated that the best results are obtained when peripheral blood is used to establish clinical predictions. Pediatric studies in AML have shown that raised WT1 levels after induction associate with unfavourable outcome. Despite all the mentioned, WT1 quantitation has not yet gained widespread use, in part because some AML show normal WT1 levels at diagnosis. To investigate the prognostic impact of the normalized bone marrow WT1 levels at diagnosis and post-induction in a consecutive series of de novo AML patients enrolled in the CETLAM group trials. Available bone marrow samples at diagnosis (586 cases) and post induction (367 cases) were obtained in each participating center and sent to the CETLAM repository center at the Hospital de la Santa Creu i Sant Pau for complete immunophenotype and molecular analyses. One μg of RNA was reverse transcribed to cDNA in a total reaction volume of 20μl containing Cl2Mg 5mM, 10× Buffer, DTT 10mM, dNTP's 10mM each, random hexamers 15μM, RNAsin 20 units (Promega) and 200 units of MMLV enzyme. WT1 expression levels were determined by real-time quantitative polymerase chain reaction (RQ-PCR) in an ABI PRISM 7700® Genetic Analyzer (Applied Biosystems, Foster City, CA) using the primers and conditions described by the ELN group (Cilloni et al J. Clin. Oncol 2009;27:5195-201). For WT1 copy number titration, the IPSOGEN® (Marseille, France) plasmid was employed. Results were expressed as copies and four normal bone marrow samples were used as test controls. Patients were treated between 2004 and 2011 according to the CETLAM03 protocol. Adults up to 70 years of age received induction chemotherapy with idarubicin, intermediate-dose cytarabine and etoposide, followed by consolidation with mitoxantrone and intermediate-dose ara-C. Subsequently, patients with favourable cytogenetics at diagnosis received one cycle of high-dose cytarabine.G-CSF priming during induction and consolidation was used. Patients with favorable cytogenetics and high leukocyte counts at diagnosis were treated with autologous transplantation instead of high-dose cytarabine. Furthermore, patients with a normal karyotype but an adverse molecular profile (FLT3 mutations or MLL rearrangements) were allocated to the treatment for unfavorable cases; this included allogeneic transplantation from an HLA-identical donor. Overall survival (OS) was measured from the date of enrolment until the date of death. Leukemia-free survival (LFS) for patients who achieved a CR was calculated from the date of CR to relapse or death. OS and LFS were plotted by the Kaplan-Meier method; differences between curves were analyzed by the log-rank test. The probability of relapse was calculated using cumulative incidence estimates and taking into account the competing risk of death in remission. A WT1 cut-off value of 5065.2 copies at diagnosis was obtained. Two hundred and four samples had WT1 levels greater than this value, whereas 382 samples showed levels below this cut-off. These groups had statistically different OS 55±3 vs 33±5 p<0.001, LFS 52±3 vs 30±6 p:0.004 and CIR 34±3 vs 56±6 p<0.001. As regards the post-induction results, four groups were established: Group 0 (135 patients) with WT1 levels between 0 and 17.5 copies, Group 1 (107 patients) with WT1 values ranging from 17.6 to 76 copies, Group 2 (54 patients) with WT1 between 76.1 and 170.5 copies and Group 3 (71 patients) with WT1 levels after induction greater than>170.6 copies. These groups showed statistically significant differences(p<0.001) in terms of OS: Group 0 59±4 months, Group 1 50±5 months, Group 2 45±7 months and Group 3 23±6 months. LFS was also statiscally different: Group 0: 58±4, Group 1: 46±5, Group 2: 39±8 and Group 3:19±8 (all p<0.001). Lastlly, CIR was markedly different between the four groups: Group 0:25±4, Group 1: 44±5, Group 2: 46±8 and Group 3: 68±8(p<0.001) . WT1 quantitation at diagnosis and post-induction provide a simple and well standardized measurement of the prognostic risk of adult AML patiens. Larger series need to be analyzed to ascertain whether this determination could be incorporated to initial AML risk stratification. Disclosures: No relevant conflicts of interest to declare.

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Mendelsohn, Laurel G., Leah Pedoeim, Eduard J. van Beers, Rehan Saiyed, James S. Nichols, Xunde Wang, and Gregory J. Kato. "Effect of Aes-103 Anti-Sickling Agent On Oxygen Affinity and Stability of Red Blood Cells From Patients with Sickle Cell Anemia." Blood 120, no. 21 (November 16, 2012): 85. http://dx.doi.org/10.1182/blood.v120.21.85.85.

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Abstract Abstract 85 Background: Aes-103 (5-hydroxymethylfurfural, 5-HMF) is a putative anti-sickling agent that has undergone pre-clinical testing for potential treatment for sickle cell anemia (SCA). It is an organic compound derived from dehydration of certain sugars, found commonly in small amounts in foods such as coffee and prunes. It binds to alpha subunits of hemoglobin and increases its oxygen affinity. At millimolar levels, it inhibits hypoxia-induced sickling in vitro and when dosed orally it protects sickle cell mice against hypoxia-induced death. We investigate the in vitro effects of a range of concentrations of Aes-103 on oxygen affinity and red cell stability in blood from healthy volunteers, and from patients with SCA with or without hydroxyurea treatment. Methods: Blood specimens from healthy control adults and adults with SCA were incubated in vitro with a range of concentrations of Aes-103 between 0.1 and 5 mM for one hour at 37 degrees C. Oxygen equilibrium curves were determined for each sample using the HemOx Analyzer. Samples were diluted in HemOx buffer and then loaded into the Analyzer, which exposed the samples to increasing partial pressure and then deoxygenated with nitrogen gas to produce the oxygen equilibrium curve. The P50 value for each curve was determined at the oxygen tension that produced 50% oxygen saturation. In additional experiments, samples of human control blood and SCA blood were treated with Aes-103 and incubated at 37°C for 1 hr, and then the samples in tubes were subjected to shear stress by rotation on a vertical rotator at 21 revolutions per minute for 3 hrs. The samples were centrifuged for 2 minutes and plasma was collected and free hemoglobin levels as an indicator of red cell membrane disruption were measured by ELISA. Results: Blood samples from SCA patients off hydroxyurea (n=6) without Aes-103 tended to have higher baseline p50 values than healthy controls (n=6)(30.3 ± 1.1 vs. 28.3 ± 0.8 torr, p=0.15), consistent with previous reports of high intracellular 2,3-DPG, known to increase P50. The P50 remained right shifted in SCA compared to controls at Aes-103 concentration below 1mM, converging with controls at higher concentrations (p=0.035). At baseline, P50 of SCA patients on chronic hydroxyurea (n=9) was significantly lower than SCA patients not on hydroxyurea (26.3 ± 0.8 vs. 30.3 ± 1.1 torr, p=0.008), compatible with the lower P50 contributed by fetal hemoglobin induced by hydroxyurea. At every concentration of Aes-103, P50 was lower for specimens SCA on hydroxyurea compared to those off hydroxyurea (p<0.001) (Figure 1A). Overall, the delta decrease in P50 from baseline in all subjects at all concentrations of Aes-103 was comparable, on regression analysis showing −2.16 torr for each mM increase in Aes-103 (r2=0.64, p<0.001). In vitro shear stress under normoxia promoted hemolysis in blood samples from patients with SCA compared to baseline (n=10, free hemoglobin 29.4 ± 3.4 vs. 8.4 ± 0.9 uM, p<0.001). Addition of Aes-103 at increasing concentrations reduced the extent of shear-stress induced hemolysis, by 15% at 1mM Aes-103; by 28% at 2mM Aes-103; and by 37% at 5mM Aes-103 (p<0.001, Figure 1B). Interestingly, although shear stress promoted less hemolysis in blood samples from healthy controls, Aes-103 at these concentrations also reduced this hemolysis to a comparable extent, suggesting a red cell stabilizing mechanism distinct from anti-sickling effect. Shear stress experiments under hypoxic conditions are underway. In pilot experiments using an imaging flow cytometry assay described in detail in a separate abstract, Aes-103 showed preliminary ability to repress sickling induced by hypoxia in vitro. Conclusions: Red cells from SCA adults treated with hydroxyurea have significantly higher affinity for oxygen than those from patients not treated with hydroxyurea, presumably related in part to the high affinity of fetal hemoglobin induced by the drug. Aes-103 increases oxygen affinity in sickle erythrocytes in a concentration-dependent fashion, and this effect is even more prominent when combined with that of hydroxyurea. Aes-103 at high concentrations stabilizes red cells against shear stress in vitro. With our collaborators at AesRx, LLC, a phase 1 safety and pharmacokinetics study of Aes-103 in healthy volunteers has been completed and we now are conducting a similar study at the NIH Clinical Center in adults with sickle cell anemia. Disclosures: No relevant conflicts of interest to declare.

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D'Souza, Pernilla, and Mark Blostein. "Report of a Case of Heyde's Syndrome Diagnosed by Abnormal Closure Times Despite Normal Von Willebrand's Activity." Blood 116, no. 21 (November 19, 2010): 1403. http://dx.doi.org/10.1182/blood.v116.21.1403.1403.

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Abstract Abstract 1403 In 1958, EC Heyde described a syndrome of iron deficiency anemia due to gastrointestinal bleeding (GI) in a patient with calcific aortic stenosis. In 1992, Warkentin et al. hypothesized a bleeding diathesis due to a link between Heyde's Syndrome and acquired Von Willebrand Syndrome. This bleeding syndrome has now been shown to result from the loss of the largest multimers of von Willebrand Factor (VWF) and is therefore classified as acquired Type 2A Von Willebrand Syndrome. Hypotheses suggest that the high shear stresses that are obtained in tortuous angiodysplastic lesions work with this deficiency of VWF, to produce gastrointestinal bleeding that is notoriously difficult to elucidate on endoscopy. It has been shown repeatedly that replacement of a stenotic aortic valve results in cessation of bleeding. Here we present a case of Heyde's Syndrome diagnosed with abnormal Closure Times and normal VWF Ristocetin cofactor activity. In this case, a 79-year-old man with known aortic stenosis and several episodes of GI bleeding was cured of a life threatening hemorrhage after the replacement of his stenotic aortic valve. At the time of his first notable gastrointestinal bleed, a tagged RBC scan showed a source of hemorrhage in the small bowel. Subsequently, two video capsule endoscopies showed jejunal angiodysplasia. After recurrent bleeding episodes, this patient presented with a life-threatening GI hemorrhage, which, in the context of aortic stenosis, raised the suspicion for Heyde's Syndrome. At this time, he presented with hematochezia requiring massive transfusions, and admission to the Intensive Care Unit. A tagged RBC scan showed active bleeding in a location that matched previous scans. The following tests were within normal limits: Factor VIII (1.53), VWF Ag (1.26), VWF:Rco activity (1.11), and the ratio of VWF Ag/VWF:Rco (0.88). However, the Dade Behring PFA-100 platelet function analyzer demonstrated that Closure Times with collagen/adenosine (> 300 sec) and with collagen/epinephrine (> 300 sec) were prolonged. In the clinical context consistent with Heyde's Syndrome, the patient's native aortic valve was replaced with a 21mm Carpentier-Edwards Magna Ease Bovine valve. As is classic for this syndrome, the valve replacement was curative. Since the surgery, the patient has not required further transfusions or interventions for gastrointestinal hemorrhage. In this case, our observations are consistent with previous reports by Warkentin et al. and Vincentellli et al. What is unique about our current report is that we measured both Ristocetin cofactor activity and Closure Times, two commonly available assays in most coagulation laboratories. Ristocetin cofactor activity is the current gold standard for measuring platelet function activity but may miss activities under high shear stress. The Closure Time, on the other hand, is able to detect defects in platelet aggregation under such conditions and may be the only manner by which such abnormalities in VWF function are detected. Therefore, we conclude that Closure Times should be used to screen for acquired Von Willebrand's Syndrome in Heyde's Syndrome. Disclosures: No relevant conflicts of interest to declare.

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Kashyap, Akriti, Gurpreet Kaur, Preeti Tripathi, and Arijit Sen. "Quality indicators in a hematology laboratory- a retrospective analysis." International Journal of Advances in Medicine 7, no. 11 (October 21, 2020): 1682. http://dx.doi.org/10.18203/2349-3933.ijam20204520.

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Background: Quality indicators are objective parameters which help to assess the effectiveness of the working system in any laboratory. Aim and objective were to study 7 common quality indicators in the hematology laboratory of a tertiary care centre.Methods: It was a retrospective analysis over a period of two and a half years (Jul 2017- Dec 2019). The following 7 QIs were analysed- sample rejection rates, sample redo rates, routine turnaround time (TAT), critical reports and their TAT, corrected reports, staining quality assessment and concordance in EQAS programme. The QI rates were calculated on monthly (or as specified) basis and trends were analysed. P value <0.05 was considered significant.Results: The final result showed average routine, urgent and critical turnaround time to be 6.5 hrs, 1.1 hrs and 3.4 hrs respectively. The other QIs were as follows - sample redo rates (3.8%), sample rejection rates (3.2%), corrected report rates (before validation– 8.5%, after validation- 1.2%) staining quality (unsatisfactory days rate- 4.5%), 98% corcordant performance in EQAS. Over the study period, a significant downward trend was noticed in TAT and sample rejection rates (p value=0.001 and 0.007 respectively). Number of monthly critical alerts showed an upward trend (p value=0.045) which could be attributed to increased awareness amongst lab staff. Redo rates showed no significant change in trend over study period.Conclusions: Quality indicators help in self-assessment and self-improvement. Their continuous monitoring is mandatory to have a tight quality check system and better clientele satisfaction.

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Langer, Florian, Susan B. Ingersoll, Ali Amirkhosravi, Todd V. Meyer, Farooq A. Siddiqui, Steve Rocca, Sarfraz Ahmad, et al. "The CD40/CD40 Ligand (CD40L) Pathway Plays a Role in Primary Hemostasis and Platelet Function." Blood 104, no. 11 (November 16, 2004): 1562. http://dx.doi.org/10.1182/blood.v104.11.1562.1562.

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Abstract Previous studies have suggested a role for platelet CD40L in thrombosis and atherosclerosis. However, there are contradictory reports on the biologic activity of its soluble variant (sCD40L) and the involved receptor signaling pathways (CD40 vs αIIbβ3). Furthermore, CD40L mAb-associated thromboembolic complications in recent human and animal studies have raised additional questions about the pro-thrombotic properties of this molecule. This study was conducted to further investigate the function of the CD40/CD40L dyad in primary hemostasis and platelet function. CD40−/− and CD40L−/− mice and mice deficient for both genes (“double knock-out”) showed prolonged tail vein bleeding and platelet function analyzer (PFA-100) closure times as compared to their wild-type littermates, indicating an inherited defect in platelet function. Recombinant human sCD40L (rsCD40L), chemical cross-linking of which yielded a single reaction product compatible with a trimeric structure of the protein in solution, bound to CD40 on resting platelets and induced CD62P (P-selectin) expression in a concentration-dependent manner (0–5 μg/ml) from 1±1 to 23±5% positivity (means±SD, n=4–8; P<0.01). This response was completely abolished by CD40 mAb M3 and not affected by blocking the β3 integrin (CD61) with abciximab. In contrast, CD40 mAb G28-5 significantly enhanced rsCD40L-induced CD62P expression to 51±5%. This agonistic effect was strongest when G28-5 was added to the platelets after rsCD40L. Pre-incubation of rsCD40L with CD40L mAb M90 also had a potentiating effect, showing an inverted V-shaped dose response curve with maximum levels of CD62P+ platelets (60–95%) at a molar M90/rsCD40L ratio of 1/3. G28-5 and M90 alone had no effect, but their combination in the presence of rsCD40L proved synergistic. Experiments with corresponding F(ab’) fragments and the FcγRII-inhibitory mAb IV.3 demonstrated that G28-5- and M90-mediated additional platelet activation resulted from signaling through FcγRII cross-linked to CD40 and rsCD40L bound to CD40 on the platelet surface, respectively. The CD40L mAb TRAP-1 showed similar characteristics to M90, but its synergistic effect with rsCD40L was less pronounced. Platelet activation by rsCD40L in combination with G28-5 and/or M90 also induced morphological shape changes, fibrinogen binding, dense granule release, microparticle generation, and monocyte-platelet-conjugate formation. Interestingly, consistent with their platelet function-modulating effects, M3 but not G28-5 prolonged PFA-100 closure times of normal human blood. This work provides genetic evidence for a role of CD40 and CD40L in primary hemostasis. Our mechanistic studies further suggest that CD40-mediated platelet activation by CD40L, in its membrane and/or soluble form, may be at least partially involved in this process. The results also offer a potential explanation for the unexpected high incidence of CD40L mAb-associated thrombotic events in patients with systemic lupus erythematosus, an inflammatory autoimmune disease characterized by elevated levels of circulating sCD40L. The underlying pathomechanism, in which sCD40L as a platelet-derived, homotrimeric protein causes multimeric clustering of bivalent antibodies on the platelet surface with subsequent FcγRII-mediated platelet activation, resembles other known immune thrombophilias such as the heparin-induced thrombocytopenia (HIT) syndrome.

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31

Seegmiller, Adam C., and Ravindra Sarode. "Increased Sensitivity of Prothrombin Time Using Recombinant Tissue Thromboplastin Reagents: Implications for Plasma Transfusion." Blood 106, no. 11 (November 16, 2005): 4058. http://dx.doi.org/10.1182/blood.v106.11.4058.4058.

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Abstract Acquired coagulopathies are often treated with fresh frozen plasma (FFP) transfusion. Standards for the tranfusion of FFP vary, but are often based on coagulation tests, especially prothrombin time (PT). Previously, the PT test was performed using tissue thromboplastin (TT) reagents derived from human or animal tissue homogenates (hTT). These preparations were fairly crude and varied between manufacturers and lots. Recently, these have been replaced with recombinant TT (rTT) reagents that are more consistent. However, anecdotal reports suggest that rTT is more sensitive to mildly decreased clotting factor levels, leading to longer PTs and increases in FFP transfusion. The purpose of this study is to test the hypothesis that rTT reagents are more sensitive and to determine if thresholds for FFP transfusion should be increased. Fifty plasma samples from patients with prolonged PTs (range 13.0–27.6 seconds; normal 9.2–12.8 seconds) were randomly selected. PTs for each sample were re-measured using rTT (Innovin, Dade-Behring, Liederbach, Germany; ISI=0.91) and hTT (Thromboplastin Reagent, Helena Laboratories, Beaumont, Texas; ISI=2.07) on the same instrument (Start 4 benchtop coagulation analyzer, Diagnostica Stago, Parsippany, New Jersey). These measured PTs are compared in Fig. 1. At the lower end of the PT range (beginning at ~13 seconds), the rTT PTs are shorter, on average, than the hTT PTs. However, the average rTT PT increases at a 1.4 times greater rate than the hTT PT, such that the average PT of the two reagents is equivalent at 16.4 seconds and longer for rTT thereafter. This suggests that the rTT reagent is indeed more sensitive. A similar pattern is seen when factor II and VII levels for each sample are plotted against the corresponding PT (Fig. 2). At high factor levels, the rTT PT is lower, on average, than the hTT PT. However, as factor levels decrease, the rTT PT rises about twice as fast as the hTT PT. The PTs for the two reagents are equivalent at 66% factor II (PT=15.7) and 46% factor VII (PT=17.7). The important thresholds for risk of surgical bleeding are 40% factor II and 25% factor VII. The equivalent PTs in this study are 20.5 (rTT) and 18.1 (hTT) for 40% factor II and 22.3 (rTT) and 19.6 (hTT) for 25% factor VII. These differences are not corrected by converting PTs to the international normalized ratio (INR). Instead, INRs are higher for hTT than rTT, and the degree of difference between the two reagents is greater. The equivalent INRs are 1.90 (rTT) and 2.54 (hTT) for 40% factor II activity, and 2.05 (rTT) and 2.98 (hTT) for 25% factor VII activity. The results of this study confirm that PTs measured using rTT are more sensitive to changes in clotting factor levels than those measured using hTT, especially at clinically significant factor levels. This suggests that thresholds for the transfusion of FFP should be raised at those institutions using rTT. Fig. 1: Comparison of PTs measured Using rTT and hTT Reagents Fig. 1:. Comparison of PTs measured Using rTT and hTT Reagents Fig. 2: Correlation of Prothrombin Time and Factor Levels Fig. 2:. Correlation of Prothrombin Time and Factor Levels

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32

Mengshol, Sarah, and Jerry B. Lefkowitz. "The APTTCan Monitor for Increased Thrombotic Risk." Blood 104, no. 11 (November 16, 2004): 3508. http://dx.doi.org/10.1182/blood.v104.11.3508.3508.

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Abstract This laboratory has been interested in the significance of short activated partial thromboplastin times (APTT) and has published work suggesting that short APTTs are associated with an increased thrombotic risk (Am J Clin Path113:123–127, 2000). Since our original publication, other workers have shown that increased levels of coagulation factor II (FII), factor VIII (FVIII), factor IX (FIX), or factor XI (FXI) are associated with an increased risk of thrombosis. Therefore, this study was designed to determine if elevated levels of FII, FVIII, FIX, or FXI might predictably result in a shortened APTT. Using a set of 30 normal plasma samples, APTT reference ranges were determined on a Stago ST4 analyzer for the following APTT reagents--Stago PTTA5, Dade Behring Actin FSL, Hemosil Synthasil, and Biomèrieux Platelin L. For this study, a short APTT was defined as being below the value of the reference range lower limit. FII, FVIII, FIX, and FXI levels were determined on a pool normal plasma in the clinical laboratory and these levels were used as a baseline to add purified factor to increase a factor activity level. The amount of factor level increase was based upon literature reports of factor levels associated with an increased thrombotic risk. A normal baseline APTT control was run for each set of assays. The coefficient of variation for control APTTs ranged from 1%–3.4% and seemed to be dependent on the specific APTT reagent. Differences were noted in the sensitivity between different APTT reagents to elevated factor levels, but all APTT reagents demonstrated the same overall trend to higher factor levels. In addition to raising individual factor concentrations, several plasmas were spiked with combinations of FVIII and FIX or FVIII, FIX, and FXI. Increasing concentrations of FVIII showed a significant decrease in the APTT, up to 3.5 seconds below the lower limit reference range at 2.2 units (U)/mL. Increasing [FIX] was associated with a trend towards a shorter APTT, but no decrease below the lower limit APTT reference range was found even with a [FIX] of 1.8 U/mL. When compared to control APTTs, increases in [FXI]<1.2 U/mL were associated with a shortening of the APTT but with [FXI]>1.4 U/ml the APTT prolonged compared to control. In no case did increases in FXI level cause the APTT to be outside of the reference range. Increasing concentrations of FII were associated with prolongations of the APTT compared to control. At the highest [FII] of 1.9 U/mL 3 of the 4 APTT reagents gave results up to 1.4 seconds above the upper limit of the reference range. When both [FVIII] and [FIX] were increased, minimal difference was seen in the APTT compared to only increased [FVIII]; however, when the concentrations of FVIII, FIX, and FXI were increased, the APTT was shortened up to 5.7 sec below the lower APTT reference range when compared to samples which had only a single factor concentration raised. These data show an association with increasing [FVIII] in plasma and shortening of the APTT. They also show that increased [FVIII] in combination with elevated levels of FIX and FXI cause a significant shortening of the APTT that exceeds a simple additive effect. These findings suggest that the APTT could be used as a screening test for elevated plasma coagulation factors, especially elevated [FVIII] which has been previously associated with an increased risk of thrombosis.

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Park, Edward, Leiqian Tai, Peggy Nakagawa, Loan Hsieh, and Diane J. Nugent. "Novel Missense Mutations Associated with FXIII Deficiency and Bleeding." Blood 114, no. 22 (November 20, 2009): 4201. http://dx.doi.org/10.1182/blood.v114.22.4201.4201.

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Abstract Abstract 4201 Introduction Factor XIII deficient patients may present at any age, with a variety of bleeding symptoms, poor wound healing, and in females, frequent miscarriages. Factor XIII (FXIII) is a transglutaminase enzyme that was first discovered as a clotting protein in the coagulation cascade, but it is now understood that it cross-links proteins in the plasma, vascular matrix, endothelial cells, platelets and monocytes. In addition to maintaining normal hemostasis, FXIII plays a role in atherosclerosis, wound healing, inflammation, and pregnancy. FXIII circulates in plasma as a tetramer protein (FXIII-A2B2) held together by non-covalent bonds. FXIII has two catalytic A subunits (FXIII-A2) of 83kd and two non-catalytic B subunits or carrier subunits (FXIII-B2) of 79kd. Mutations have been identified in almost every exon of the FXIIIA subunit and often are unique to a particular cohort or family with Factor XIII deficiency. Our center has been characterizing patients with FXIII deficiency and has an IRB approved study to characterize bleeding phenotype in relation to genotype or mutational analysis. As part of this effort, we have identified 3 novel missense mutations, which we have not found in the FXIII database (<www.f13-database.de>) or in previous publications. Methods After obtaining informed consent, venous blood was collected in EDTA tubes for DNA isolation, PCR and ultimately DNA sequencing. DNA was isolated using QIAamp DNA Blood Midi Kit (Qiagen, Germantown, MD). Customary PCR was used to amplify the 15 exons for subunit A and the 12 exons for subunit B, using sequence specific primers based on previous publication and created to initiate outside of the encoding sequence. The nucleotide sequencing of amplified products was obtained via ABI 3730 DNA Analyzer (UCLA Sequencing and Genotyping Core). Results All three novel mutations were found in three, separate, unrelated individuals, with FXIII deficiency diagnosed early in life with a moderate to severe bleeding. Using the methods described above, the DNA sequencing and analysis for all exons for both the A and B subunits revealed three novel mutations, two on exon 12 subunit A and one on exon 10 subunit A. Patient 1 has a novel missense mutation in exon 10 at the 427 amino acid position, changing the aspartic acid into an asparagine (Asp427Asn) in the catalytic core. Patient 2 and 3 each had a unique mutation in exon 12. Exon 12 covers the transition from the catalytic core region and the Barrel 1 region of the FXIIIA molecule thus including portions of each functional region. Patient 2: An exon 12 missense mutation in aa 501 resulting in a change from glycine to an arginine (Gly501Arg) still in the catalytic core region. Patient 3 also had a mutation in exon 12 but in position 576 resulting in an amino acid change from threonine to methionine (Thr576Met) now in the Barrel 1 region. Patient 2 also had a missense mutation that has been previously reported in exon 3 (Arg77His) in the β-sandwich region. Three new missense mutations have been identified in patients with severe Factor XIII deficiency and a bleeding disorder. Previous reports of other point mutations in the FXIIIA catalytic core and barrel 1 regions have also been described in association with a hemorrhagic state in deficient patients. Ongoing protein expression studies will aid in our understanding of how these single amino acid substitutions result in such a serious bleeding diathesis. Disclosures: No relevant conflicts of interest to declare.

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Parrow, Nermi, Pierre-Christian Violet, Nisha George, Faris Ali, Shivam Bhanvadia, Mark Levine, and Robert E. Fleming. "Iron Restriction Improves Markers of Disease Severity in the Townes Mouse Model of Sickle Cell Anemia." Blood 134, Supplement_1 (November 13, 2019): 2261. http://dx.doi.org/10.1182/blood-2019-130732.

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Introduction: Sickle cell anemia (SCA) is caused by mutations in β-globin that result in the production of the abnormal hemoglobin, HbS, with deleterious effects on erythrocyte shape and life span. Because the propensity of erythrocytes to sickle is inversely proportional to the concentration of HbS in the cell, decreasing the mean cellular hemoglobin concentration (MCHC) represents a potential therapeutic approach. Whereas iron restriction in healthy individuals does not alter MCHC, concomitant iron deficiency has been associated with decreased MCHC in SCA patients. Isolated case reports have linked iron restricted erythropoiesis with decreased hemolysis, increased red cell lifespan, and improvement in certain outcomes in SCA patients. We systematically examined the effects of iron restriction on erythropoietic outcomes in SCA utilizing the Townes murine model to investigate the hypothesis that mice with dietary iron deficiency will demonstrate a decreased MCHC, decreased erythrocyte sickling propensity, and improved anemia compared with mice on an iron sufficient diet. Methods: Townes SCA mice were weaned to diets containing either 20 ppm iron (low) or 48 ppm iron (sufficient) and maintained on those diets until sacrifice at 2 months of age. Blood was collected for complete blood count by submandibular or cardiac puncture. Spleen weight was normalized to body weight for calculation of the splenic index. Red cell deformability, defined by the elongation index (EI), and the oxygen pressure at which sickling occurs (point of sickling) during deoxygenation were characterized by oxygenscan ektacytometry using a laser optical rotational red cell analyzer (Mechatronics, The Netherlands). Results: SCA mice fed a 20 ppm low iron diet demonstrate a significant decrease in MCHC compared to SCA mice fed a 48 ppm iron sufficient diet (17.7+1.1 vs 22.7+5.5 g/dL; p <0.05). Mice fed the low iron diet produced more circulating RBCs (5.98+1.03 vs 4.61+0.84 x 106 cells/uL; p <0.05) and a higher hematocrit (39.4+7.1 vs 24.6+4.6%; p <0.05) with a corresponding decrease in splenic index (0.074+0.14 vs 0.087+0.006 g/g body weight; p <0.05) compared to mice fed the iron sufficient diet. RBCs from mice fed the low iron diet showed a significant decrease in the oxygen pressure at the point of sickling compared to RBCs from mice fed the iron sufficient diet (31.9+4.7 vs 40.6+4.6 mmHg; p <0.01). The low iron diet also resulted in an overall improvement in deformability as evidenced by an increase in the EI minimum compared to the iron sufficient diet (0.25+.07 vs 0.12+.03 au; p <0.01). No significant differences between groups were found in maximum deformability (EI max). The improved EI minimum translates to a decreased change in elongation (Delta EI), defined as EI max minus EI min, in RBCs from mice fed the low iron diet compared to mice fed the iron sufficient diet (0.11+.08 vs .23+.02 au; p <0.01). Conclusions: Decreased dietary iron intake is associated with a decrease in the MCHC in Townes SCA mice. The lower MCHC is accompanied by an amelioration of anemia, decreased extramedullary erythropoiesis, improved RBC deformability and a shift in the initiation of sickling to lower oxygen pressures during deoxygenation. We speculate that iron restriction may decrease the clinical complications arising from both hemolysis and sickling in SCA. Future studies will utilize this model system to further characterize the effects of manipulating iron homeostasis on erythropoietic outcomes in SCA. Disclosures Fleming: Protagonist: Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Consultancy; Ultragenyx: Consultancy.

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Konstandin, Nikola P., Annika Dufour, Philipp A. Greif, Bianka Ksienzyk, Alexander Graf, Stefan Krebs, Helmut Blum, et al. "Whole Exome Sequencing of CLL Before Second-Line Treatment with Fludarabine and Cyclophosphamide with or without Rituximab (REACH trial)." Blood 120, no. 21 (November 16, 2012): 2514. http://dx.doi.org/10.1182/blood.v120.21.2514.2514.

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Abstract Abstract 2514 Chronic lymphocytic leukemia (CLL), the most frequent leukemia in adults, still remains poorly understood. Several prognostic markers like the deletion of certain genomic regions as assayed by fluorescence in situ hybridization (FISH), the mutational status of the IGVH locus or the expression levels of ZAP70 have been identified. However, the predictive power of these markers is limited and they cannot fully explain the heterogeneity and the biology of CLL. The addition of monoclonal anti-CD20 antibody (rituximab) to chemotherapy has significantly improved progression-free survival of CLL patients even at second-line treatment (Robak et al. JCO 2010). The aim of our project was to identify new, potentially predictive markers in previously treated patients that reached complete remission after second-line treatment with FC or R-FC (Fludarabine, Cyclophosphamide and Rituximab). We performed whole exome sequencing in 25 CLL samples before second-line treatment and their corresponding disease free remission samples (peripheral blood). Disease free remission was defined as minimal residual disease levels of less than 1×10−3 as measured by the disease specific IGVH rearrangements using quantitative PCR and FISH negativity if a marker was available. The CLL samples had a median of 84% CD19 positive cells. Our CLL patients had a predominance of favorable prognostic markers, 60% being IGVH mutated, 52% with a sole 13q deletion and 16% with a trisomy 12. Only 8% had a prognostically unfavorable 11q deletion, none had a 17p deletion or more than one FISH abnormality (the following genomic regions were analyzed: 6q, 13q, 11q (ATM), trisomy 12, 17p (TP53)). The exomes of the paired CLL and disease free remission samples were captured using the Agilent Sure Select 50 Mb kit (Agilent Technologies, Santa Clara, CA, USA). Sequencing was performed with 76–80 bp paired-end reads on an Illumina IIx Genome Analyzer (Illumina, San Diego, CA, USA). The mean total sequence per exome was 6.6 Gbp, of which >80% could be aligned to the reference genome (build NCBI36/hg18). About 90% of all SureSelect exome target positions were covered ≥ 10 fold. We called single nucleotide variants (SNVs) specific for the CLL samples using VarScan (Koboldt et al Bioinformatics 2009) with custom filter settings. Annotated polymorphisms (dbSNP130) were excluded. About 80% of the SNVs that were predicted to result in a missense or nonsense mutation could be validated by Sanger sequencing. In total we detected 208 somatic missense or nonsense mutations in 198 genes in the 25 CLL exomes. Four genes were found mutated in more than one CLL sample indicating that these might be drivers for CLL. We also compared our gene list with published CLL exome and genome data to identify additional recurrently mutated genes. A total of 2756 mutated genes (harbouring non-synonymous, InDels and splice site mutations) have been described in 200 CLL patients which were predominantly analyzed at first-line treatment (Wang et al NEJM 2011, Puente et al Nature 2011 and Quesada et al Nature Genetics 2012). Within these three public datasets 369 genes were recurrent (found mutated in more than one sample). In our dataset 129 out of 198 mutated genes have not been described as mutated in these three publications. The remaining 69 genes were previously found to be mutated in CLL. Out of these 69 genes 37 can only be identified as recurrent when our data set is taken into consideration. Thus, our study increases the number of recurrently mutated genes in CLL from 369 to 406. We detected three samples with XPO1 mutations; all of which had a non-mutated IGVH status, two had a 13q deletion and one had no FISH aberration. Two patients in our cohort had SF3B1 mutations; both patients had an unmutated IGVH status; one with a 13q deletion and one with no FISH aberration. 24 out of the 25 patients had at least one recurrent mutation taking the public datasets in consideration. Our results are in agreement with other published whole exome and whole genome sequencing reports of CLL and reinforce the picture that CLL is genetically a very heterogeneous disease. In fact, almost all large scale sequencing studies of cancer genomes and exomes indicate that the number of biologically relevant mutational targets is much larger than expected. Our results also highlight the necessity to perform whole exome or whole genome sequencing on ever larger numbers of CLL samples. Disclosures: Konstandin: Roche: Research Funding. Krebs:Illumina: Honoraria. Trunzer:Roche: Employment. Weisser:Roche: Employment.

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Patel, Mira, Donna Oksenberg, Abel Silva, Andreas Betz, Brian Metcalf, and Uma Sinha. "GTx011, a Novel Agent That Improves Rheological Properties Of Sickle Cell Blood By Increasing Oxygen Affinity For Hemoglobin." Blood 122, no. 21 (November 15, 2013): 2207. http://dx.doi.org/10.1182/blood.v122.21.2207.2207.

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Abstract Sickle cell disorder (SCD) is characterized by the presence of non-deformable red blood cells. Literature reports indicate that the T-state structure of hemoglobin (Hb) (highly correlated with the deoxy form) is responsible for the formation of HbS polymers that lead to rigid cells. We hypothesized that the likelihood of polymer formation will be reduced if sufficient HbS remains in the R-state (oxy) conformation. We have designed and synthesized a novel series of compounds that increase the O2 affinity of HbS and improve the rheological properties of SCD blood. In a novel 96-well format oxygen dissociation assay (ODA), compounds including GTx006, GTx007 and GTx011 were all more potent than 5-hydroxy furfural (5HMF), an agent being tested in clinical trials in SCD patients. After two hours of passive deoxygenation, GTx011, at an equimolar concentration to Hb, increases the O2 affinity by six-fold and drastically delays polymerization of HbS. Even at substoichiometric concentrations (GTx011:Hb= 1:3) GTx011 elicits a two-fold improvement in O2 affinity for Hb that translated to 16% more oxy-Hb relative to control (Table 1). We then analyzed the agents in a TCS Hemox analyzer using purified Hb at 25µM. At a GTx011:Hb ratio of 1:3 the oxygen affinity was improved by 15%, while at stoichiometric concentrations, the oxygen affinity was increased by 70% compared to Hb control. These biochemical assays indicated that the GTx agents were altering Hb O2 affinity and should therefore assist in maintaining the oxy conformation of Hb and prevent the formation of polymers.Table 1AssayHb in ODAWashed RBC OECWhole Blood OECViscosityunit(Δoxy state)(%Δp50)(%Δp50)(ΔcP)[Hb]3 µM1 mM1 mM1.5 mM[cmp]1 µM3 µM1 mM3 mM1 mM3 mM1.6 mM8 mM5-HMF<1<1306510470.042.4GTx006210597849711.7>2.5GTx007623697863>802.1>2.5GTx0111656768380>802.5>2.5 To test the agents in a more physiological system, oxygen equilibrium curves (OECs) were measured in washed red blood cells (RBCs) and in whole blood at 20% hematocrit (∼1 mM Hb). In washed RBCs, 5HMF, GTx006, GTx007 and GTx011 at a concentration of 1mM produced partial O2 pressures (p50) of 20, 12, 9 and 7 mm Hg, respectively (control RBCs = 30 mm Hg). To determine the effects of plasma proteins, OECs were measured in whole blood from SCD patients, giving p50s of 27, 18, 11 and 6 mm Hg compared to the control blood p50 of 30 mm Hg (agent concentration of 1 mM). Table 1 shows that 5HMF and GTx006 activities were affected by the presence of plasma proteins but GTx007 and GTx011 activities were not altered. SCD patients develop anemia due to hemolysis, which partially compensates for an increase in blood viscosity caused by the non-deformable RBCs (ssRBCs). We monitored the effect of our agents on SCD patient blood rheology, ex vivo, to determine if they were capable of decreasing the viscosity of SS blood under hypoxic conditions. We incubated whole blood from SCD patients (30% hematocrit, ∼1.5 mM Hb) with 5HMF, GTx006, GTx007 or GTx011 for 30 mins and then subjected the blood to 2 hours of hypoxia (2.4% O2). Blood viscosity was then measured in a cone-plate viscometer at shear rates ranging from 60 s-1 to 415 s-1. Of the four compounds, GTx011 showed the most pronounced improvement in rheologic measures (see Table 1), changing the viscosity from 6.46 cP (no GTx011) to 4.00 cP (equimolar GTx011). Normoxic SCD blood had a viscosity of 4.28 cP. A similar improvement in blood viscosity under physiologic conditions may be predicted to decrease the residence time of ssRBCs in hypoxic tissue, and allow for a lower level of polymerization in individual red blood cells. In addition, GTx011 has also been shown to delay polymerization and delay sickling. Thus, GTx011 has the potential to elicit a decrease in HbS polymer concentration, reducing the likelihood of forming the rigid cells that cause vaso-occlusion in SCD patients. Disclosures: Patel: Global Blood Therapeutics: Employment, Equity Ownership. Oksenberg:Global Blood Therapeutics: Employment, Equity Ownership. Silva:Global Blood Therapeutics: Employment, Equity Ownership. Betz:Global Blood Therapeutics: Employment, Equity Ownership. Metcalf:Global Blood Therapeutics: Employment, Equity Ownership. Sinha:Global Blood Therapeutics: Employment, Equity Ownership.

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Aung, Ye Myint, Aynur Aktas, Vishal Shroff, Kunal C. Kadakia, Jake Waldman, and Declan Walsh. "Nutrition assessment reports in oncology clinical trials." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): e24142-e24142. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e24142.

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e24142 Background: Malnutrition is common in cancer and associated with greater treatment toxicity and poor clinical outcomes. Validated screening tools can identify individuals at risk; however, they are underutilized in clinical practice. It is also unclear how nutrition status is assessed and reported in oncology clinical trials. We analyzed nutrition assessment protocols in clinical trials published in major US oncology journals. Methods: Three researchers (YA, AA, VS) identified studies published in the Journal of Clinical Oncology, JAMA Oncology, and the New England Journal of Medicine under the “original reports”, “original articles”, or “’ research” categories, respectively (1/1/2022-12/31/2022). We selected studies that reported outcomes of systemic therapeutic interventions in any Phase clinical trial. This included chemotherapy, hormone therapy, and immunotherapy alone or combined with radiation therapy or surgical procedures. Systematic reviews, meta-analyses, commentaries, retrospective studies, and secondary analyses of pooled data from completed trials were excluded. Descriptive statistics summarized how malnutrition risk was assessed and nutrition data reported. Results: 521 articles were reviewed; 153 (29%) studies met eligibility criteria. Most were randomized trials (103/153, 67%) and Phase II or III (126/153, 82%). Malnutrition risk assessment was absent from all studies. Overall, 15/153 (10%) reported either baseline Body Mass Index or pre-treatment weight changes. These variables were included in the survival analysis of 5/15 studies. The primary cancer sites studied were breast (5/15), gynecologic (3/15), hematologic (3/15), multiple sites (2/15), prostate (1/15), and pancreatic (1/15). Conclusions: Most oncology clinical trials ignore and/or underreport nutrition status. Only 10% of the studies reported nutrition status data, and not all cancer sites were represented. There is a need to routinely assess nutrition status and (given the major prognostic value) investigate its potential uses for patient selection and stratification in clinical trials.

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Ray, Rudra, Ankita Biswas, Sunistha Bhattacharjee, and Maitreyee Bhattacharyya. "Phenotypes of Hb Okayama Mutation." Blood 132, Supplement 1 (November 29, 2018): 4898. http://dx.doi.org/10.1182/blood-2018-99-118079.

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Abstract Introduction: Since its first detection in the year of 1983 very little has been reported about Hb Okayama mutation. Hb Okayama, reported as a silent mutation (Globin Gene Server Hb Var ID: 220, dbSNP rs713040), happened to be detected in the process of HPLC analysis for the measurement of HbA1c in Japanese diabetic patient [1,2,3]. Till date only few Hb Okayama has been reported from Japanese and Austrian ethnicity [2,3,4]. Its phenotypes and co-inheritance with other beta globin gene mutation is not yet known. In this study we report phenotypes of Hb Okayama in heterozygous as well as compound heterozygous state when it is co-existing with a common beta globin gene mutation. To the best of our knowledge no such study has been reported in world literature. Methodology: Two groups of patients- beta carriers requiring blood transfusion; and patients with low MCV, MCH but normal in HPLC were further investigated by molecular analysis. ARMS PCR analysis for beta globin gene mutation detection, GAP PCR for alpha deletion and triplication analysis and DNA sequencing (ABI 3500 Genetic Analyzer) to identify rare beta mutations were carried out. Result: Among around 300 patients subjected to molecular investigation over last three years there were 118 cases of thalassaemia trait (by HPLC and confirmed to carry a heterozygous common beta mutations by ARMS PCR analysis), but were requiring blood transfusion or behaving like intermedia. They were subjected to alpha globin gene triplication analysis by GAP PCR. There were 84 cases found to carry absence of alpha triplication with heterozygous beta mutation. Beta globin gene sequencing analysis of these 84 patients revealed that there were 4 patients carrying Okayama heterozygous mutation [ Figure 1, Figure 2 ] along with a common heterozygous beta gene mutation ( IVS 1-5 G>C mutation). HPLC report of these patients carrying Hb Okayama along with IVS 1-5 mutations in compound heterozygous state showed increased HbA2 values like that of beta trait [Table 1 ]. Another group of patients with low MCV, MCH but Normal in HPLC were subjected to alpha deletion analysis after ruling out low Ferritin level. There were 72 patients showing absence of alpha deletion by GAP PCR analysis and carried low MCV, MCH value with Normal HPLC parameters were also subjected to beta globin gene sequencing which revealed the presence of Hb Okayama mutation among two patients in heterozygous state [Figure- 1, Figure 2], who had HbA2 values in normal or border line range with low MCV, MCH levels [Table-2]. Discussion: HbA2 measurement is used as the marker for screening of beta trait. Silent beta-thalassaemia carriers represent normal HbA2 level which makes their identification difficult. Okayama mutation or Hb Okayama is known to be a silent mutation [1-4] with normal HPLC. Hb Okayama is structural beta variant with a change of amino acid ( His > Gln) at Codon 2 (CD 2). Change in the nucleotide sequence at 70603 position from T to A or C (CAT>CAA or CAG) of beta globin gene (NG_000007.3) causes this mutation. The phenotypic associations of Hb Okayama in thalassaemia have very little been known till date. There has been report of very high expression of HbF(70%) value in HPLC resulting from compound heterozygous mutations one of which being silent (Cap+1) [ 5] ; where as there are also reports where the phenotypes of compound heterozygous including a silent mutation showing normal HPLC parameters [ 6 ]. However, in those studies no information about the clinical history and blood transfusion is described. In this study Hb Okayama heterozygous co-inheriting with IVS1-5(G>C) heterozygous mutation showed beta trait like HPLC parameters though all the patients carrying these compound heterozygous mutations required blood transfusion. The silent feature of Hb Okayama was evident in the case of the patients carrying only Hb Okayama mutation who showed absolutely normal HPLC parameters with low MCV, MCH and none of them requiring blood transfusion. Conclusion: Beta globin gene expression analysis to understand the association of Hb Okayama mutation in heterozygous and compound heterozygous states will enable to explain the mechanism of its phenotypes. How this mutation interferes with the expression of HbF or switching of delta globin gene is also to be understood as the HbF levels in HPLC was found to be like beta traits in this study. Disclosures No relevant conflicts of interest to declare.

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Callado, Antônio André Cunha, and Fábia Michelle Rodrigues de Araújo Callado. "Operational performance and budget constraints: case study in a Public Hospital specialized in Hematology." Management Control Review 7, no. 1 (June 2, 2023): 28–37. http://dx.doi.org/10.51720/mcr.v7i1.5469.

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The objective of this paper is to analyze the impact of budget constraints of the Brazilian public sector on operational performance indicators in a hematology specialized Hospital. In order to carry out this research a case study approach was designed considering average length of stay, occupancy rate, hospital mortality rate. Data regarding results of these indicators were obtained considering two periods of time. The first period was from January 2013 to December 2014 and the second period was from January 2015 to September 2016. Expected performance reference values from these indicators were also obtained. Data were obtained from official performance reports. The starting point for budget constraints considered was January 2015. Descriptive statistics was used to present the operational performance obtained. Mann-Whitney U test was used to analyze the presence of significant differences (p=0.05) in operational performance for the performance indicators considered. The results point out that, despite budget constraints, the operational performance regarding occupancy rates and hospital mortality rate did not presented statistically significant differences. Average length of stay was higher in the second period.

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Eremina, Yuliana Olegovna, and Cacilda Magalhães. "Reticulocyte haemoglobin content: 2020 update." I.P. Pavlov Russian Medical Biological Herald 28, no. 4 (December 15, 2020): 605–12. http://dx.doi.org/10.23888/pavlovj2020284605-612.

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The hemoglobin content of reticulocytes (Hb-ret) is an effective real-time hemoglobin synthesis status indicator that permits diagnosis and monitoring of iron deficiency and iron deficiency anemia in all age groups with or without underlying diseases, including beta thalassemia. Hb-ret is less invasive than bone iron examination, less expensive than iron biochemical tests and might be available even in local laboratories. This review covers reports published mainly in 2020 and some other studies dedicated to clinical application of Hb-ret measured by Sysmex hematology analyzers.

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Krieg, Marion, Hugo H. Marti, and Karl H. Plate. "Coexpression of Erythropoietin and Vascular Endothelial Growth Factor in Nervous System Tumors Associated With von Hippel-Lindau Tumor Suppressor Gene Loss of Function." Blood 92, no. 9 (November 1, 1998): 3388–93. http://dx.doi.org/10.1182/blood.v92.9.3388.

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Abstract Hemangioblastomas are highly vascular tumors of the central nervous system that overexpress the hypoxia-inducible gene, vascular endothelial growth factor (VEGF), as a consequence of mutational inactivation of the von Hippel-Lindau tumor suppressor gene (VHL). Previous reports showed that hemangioblastomas can also express erythropoietin (Epo), which is also hypoxia-inducible. However, Epo expression in hemangioblastomas was observed only in individual cases, and the analyses were mainly based on indirect determination of erythropoiesis-stimulating activity. Therefore, we analyzed a series of 11 hemangioblastomas for Epo, VEGF, and VHL expression by Northern blot analysis and compared the results with normal brain and glioblastomas. Surprisingly, we observed Epo mRNA expression in all hemangioblastoma specimens analyzed, but in none of four glioblastomas. In contrast, VEGF mRNA was expressed in all hemangioblastomas and all glioblastomas. In situ hybridization revealed neoplastic stromal cells as Epo- and VEGF-producing cells in hemangioblastomas. These results suggest that in the nonhypoxic microenvironment of hemangioblastoma, Epo, similar to VEGF, might be negatively regulated by the VHL gene product. © 1998 by The American Society of Hematology.

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Krieg, Marion, Hugo H. Marti, and Karl H. Plate. "Coexpression of Erythropoietin and Vascular Endothelial Growth Factor in Nervous System Tumors Associated With von Hippel-Lindau Tumor Suppressor Gene Loss of Function." Blood 92, no. 9 (November 1, 1998): 3388–93. http://dx.doi.org/10.1182/blood.v92.9.3388.421a09_3388_3393.

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Hemangioblastomas are highly vascular tumors of the central nervous system that overexpress the hypoxia-inducible gene, vascular endothelial growth factor (VEGF), as a consequence of mutational inactivation of the von Hippel-Lindau tumor suppressor gene (VHL). Previous reports showed that hemangioblastomas can also express erythropoietin (Epo), which is also hypoxia-inducible. However, Epo expression in hemangioblastomas was observed only in individual cases, and the analyses were mainly based on indirect determination of erythropoiesis-stimulating activity. Therefore, we analyzed a series of 11 hemangioblastomas for Epo, VEGF, and VHL expression by Northern blot analysis and compared the results with normal brain and glioblastomas. Surprisingly, we observed Epo mRNA expression in all hemangioblastoma specimens analyzed, but in none of four glioblastomas. In contrast, VEGF mRNA was expressed in all hemangioblastomas and all glioblastomas. In situ hybridization revealed neoplastic stromal cells as Epo- and VEGF-producing cells in hemangioblastomas. These results suggest that in the nonhypoxic microenvironment of hemangioblastoma, Epo, similar to VEGF, might be negatively regulated by the VHL gene product. © 1998 by The American Society of Hematology.

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Zhiguleva, L. Yu. "Current structure, organization and evaluation of effectiveness of the specialized outpatient medical care for patients with blood diseases in a metropolis." Kazan medical journal 95, no. 2 (April 15, 2014): 261–67. http://dx.doi.org/10.17816/kmj2077.

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Aim. To analyze the structure, organization and effectiveness of outpatient medical care for patients with blood diseases in St. Petersburg, Russia. Methods. 83 reports submitted by the heads of hematological offices at 2000-2012 were analyzed. The effectiveness was evaluated using routine statistical tests. The prevalence of the diseases was assessed by registration forms №7, 35, the data provided by information and analytical center of the Healthcare Committee and the City cancer registry. Medical aid provided to patients at 2010-2012 was studied, for this purpose 250 outpatient files (025/y form) were randomly picked out, the data were collected using specially designed registration cards (254 parameters). Results. Municipal, federal and departmental institutions provide hematologic outpatient medical care in St. Petersburg. The major burden of providing medical care to hematologic patients lays on interdistrict hematological offices, which actively follow-up and treat patients with hematologic cancers. Every sixth patient has complications, and 75% - comorbidities. During the period of study, the attendance rate increased by 33.4% (from 64 766 in 2000 to 86 405 in 2012), the number of the newly-diagnosed patients with hematologic cancers increased by 13.9% (p 0.05), the share of patients with hematologic cancers increased from 28.0 to 50.4%. Cumulative incidence of lymphomas increased from 69.9 to 96.0 per 100 thousand of population; leukemia - from 49.7 to 79.3. Mortality due to lymphomas decreased from 8.1% in 2001 to 5.3% in 2012, and due to leukemia - from 9.2% to 3.6%. Five-year survival rate of patients with leukemia increased from 56.6% to 63.2 % over the period of 2010-2012. Conclusion. The study shows the effectiveness of outpatient hematologic care in St. Petersburg. To further improve the efficiency of outpatient hematologic care in metropolis, it is important to improve the knowledge of hematologic diseases by doctors and pediatricians of general healthcare network, to review the workload of hematological office staff, to focus on preventive component of hematologic care (quality of occupational medical examinations), to develop and implement the new organizational techniques providing costs reduction and improving quality of life.

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Yassin, Mohamed A., Ashraf Tawfiq Soliman, Feryal Abbas, Abdulqadir Jeprel Nashwan, Mahmood B. Aldapt, Mohammad Abdul-Jaber Abdulla, Saloua Hmissi, et al. "Hematological Indices Reference Intervals for Healthy Arab Population in Qatar: Effect of Age, Gender, Geographic Location and ABO Blood Group." Blood 136, Supplement 1 (November 5, 2020): 22–23. http://dx.doi.org/10.1182/blood-2020-134424.

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Introduction: The majority of physicians' medical judgments are based on clinical information supported by laboratory reports . The availability of a reference interval for different lab values facilitates the process of interpretation . Complete blood count (CBC), testing is one of the most frequently performed hematology test in any clinical setting. Analysis of CBC by hematology analyzers is an indispensable means in the evaluation of many acute and chronic disorders including traumatic, infectious, immunological, and hematological diseases. Establishment of a normal reference interval is essential for accurate clarification of the disease diagnosis as well as for follow up. CBC techniques have improved significantly, and the accurate automated methods have now substituted manual methods. In addition, various novel blood cell parameters have been developed alongside to aid in diagnosis and management of several blood disorders . However significant differences exist in the reference intervals based on age, gender, ethnicity, genetic differences, environmental factors, and geographical location.. Dietary habits and occupational exposures are factors that have been shown to affect reference interval . Therefore, there is a requirement for each country to establish its own reference intervals. Country-specific reference intervals for CBC of adult peripheral blood have been established in many countries around the world; however, there have been no specific comprehensive studies in Arab population in Qatar based on age, gender, geographic location and ABO blood groups. To the best of our knowledge, this is the first study in Qatar that investigated CBC reference intervals in relation to age, gender, and blood grouping which can now be used as a reference when evaluating patient samples in Qatar. Methods: Venous blood specimens were collected from 720 healthy randomly selected individuals aged 18 to 69 years from 2018 to 2019 and analyzed by Sysmex NX-10 and NX -20 automated hematology analyzers. Results were statistically analyzed and compared by gender, age, and ABO blood group. Arab adults were divided into African Arabs (Egypt, Libya, Tunisia, Morocco) and Asian Arabs (Syria, Lebanon, Jordon, Palestine, Qatar). The lower and upper reference limits of the hematology reference intervals were established at the -2 SD and +2SD respectively. Results: Reference intervals were calculated for all the hematology parameters which included red blood cell, white blood cell and differential count, and platelet parameters. Arab males had significantly higher Hb, Hct, RDW, ANC, lymphocytes and monocyte counts compared to adult females. Asian-Arab males had significantly higher Hb concentration and higher WBC, lymphocytes and eosinophil counts compared to African- Arab males. Asian Arab young males had significantly higher Hb level and lymphocyte count and lower monocytes counts compared old males. African Arab young males had significantly higher lymphocyte and lower monocytes counts compared to old males. Asian- Arab young females had higher WBC, ANC counts compared to old Asian Arab females. No statistical difference in the studied hematological parameters was detected among the three groups with different ABO subgroups Conclusions: Data from this study established specific reference intervals which could be considered for general use in the Arab world. The differences in hematology reference intervals in respect to age, sex and geographical location highlights the necessity to establish reference intervals for venous blood parameters among the healthy population in each country or at least in each region. Disclosures No relevant conflicts of interest to declare.

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Silva, Vanessa Rafaella Foletto da, Patricia Pereira Serafini, Joice Reche Pedroso, Denise Pereira Leme, and Vanessa Tavares Kanaan. "Hematologic reference values of Vinaceous-breasted Amazon (Amazona vinacea)." Ciência Rural 46, no. 12 (December 2016): 2135–41. http://dx.doi.org/10.1590/0103-8478cr20160023.

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ABSTRACT Avian hematologic reference intervals are useful tools to evaluate body homeostasis and diagnose diseases. However, there are few species-specific reference intervals published. The present study reports Vinaceous-breasted Amazon ( Amazona vinacea ) hematologic reference values obtained during the health status evaluation of release candidates as part of this species reintroduction efforts at the Araucárias National Park. Parameters reported are erythrogram (erythrocytes, hemoglobin, packed cell volume, mean cell volume, mean corpuscular hemoglobin concentration and mean corpuscular hemoglobin), Red Cell Distribution Width (RDW), white cells total and differential (heterophiles, lymphocytes, basophils, eosinophils and monocytes), thrombocytes and total plasma protein. For the first time results on RDW and thrombocytes were described and a larger sample size were provided for all parameters analyzed. Intervals demonstrated in the present study showed significant differences from those considered normal in other parrot species and consequently have contributed to bring valuable information to base actions for the conservation of this endangered species of great biological value.

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Richey, Elizabeth A., Veena Shankaran, Steven Hirschfeld, Steven M. Trifilio, June McKoy, Kenneth R. Carson, Beatrice J. Edwards, et al. "“Getting to go” for FDA Approvals for the Treatment of Hematologic Versus Solid Tumor Malignancies: A Report from the Research on Adverse Drug Events and Reports (RADAR) Project." Blood 112, no. 11 (November 16, 2008): 2402. http://dx.doi.org/10.1182/blood.v112.11.2402.2402.

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Abstract Background: The accelerated approval (AA) regulation (21CFR314.510 Subpart H) is granted by the Food and Drug Administration (FDA) when drugs for serious medical illnesses are shown to be an improvement over available therapy. AA provides an option to use surrogate outcomes considered likely to predict clinical benefit. AA was initially developed to hasten access to HIV drugs, then, in 1995, AA was extended to cancer indications. Sponsors receiving AA are required to confirm clinical benefit (termed subpart H trials). Policy makers have several raised concerns: AA is no longer relevant today as the approval bar via this mechanism has been raised too high; many drugs that received AA did not complete subpart H trials; and some drugs approved by AA were subsequently found to be unsafe or ineffective. Methods: Using publicly available databases, we compared safety, efficacy, clinical development times, and subpart H completion rates for FDA-approved new molecular entities (NMEs) for hematologic and solid tumor cancers from 1995–2008. Results: 37% of all oncology NMEs received AA versus regular approval (64% during 1995–2003 and 33% during 2004–2008). Twenty oncology NMEs received FDA approval for hematologic malignancies (lymphomas, leukemias, Kaposi’s sarcoma, and myelodysplastic syndromes), accounting for 34% of regular approvals and 53% of AAs for oncology NMEs. Compared to NMEs approved for solid tumors, NMEs approved for hematologic malignancies were more likely to involve Orphan Drug indications (95% vs. 32%); to have shorter development times, defined as the interval between investigational new drug filing and marketing approval, (median 5.6 vs. 7.8 years); and to be approved based on phase II studies (65% vs. 29%). Prior to 2004, development times were similar for solid tumor and hematologic malignancy NMEs. Since 2004, development times have decreased by more than 2 years for hematologic malignancy NMEs, but not for solid tumor NMEs. 50% of NMEs approved for hematologic malignancies versus 71% of NMEs for solid tumor diagnoses are included in first-line cancer regimens in current National Comprehensive Cancer Network guidelines. Drugs approved for solid tumor and hematologic indications have similar safety profiles and efficacy; respectively, 30% and 38% carried black box warnings at initial approval, and 15% and 10% had black box warnings added post-approval. Studies confirming efficacy were completed for 89% of NMEs receiving AA for solid tumor indications versus 30% for NMEs receiving AA for hematologic malignancy indications. Concern that sponsors are not completing subpart H commitments has led the FDA to move from basing AA on final results of single-arm phase II trials to interim results of phase III trials. Conclusions: AAs for hematologic malignancy indications are less likely to complete Subpart H commitments. In the current era, development times for NMEs are shorter for hematologic malignancy versus solid tumor indications, principally related to the approval based on Phase II versus Phase III studies. Establishing a global policy that AA approval for cancer drugs should be based on interim results of phase III analyses rather than on final analyses of phase II trials may hamper development of novel therapies for hematologic malignancies. Solide tumor indications Hematologic malignancy indications 1995–2003 (n=21) 2004–2008 (n=10) 1995–2003 (n=11) 2004–2008 (n=9) Drugs receivving AA (%) 29 30 64 33 Orphan drugs (%) 24 40 100 78 Of AAs, Subpart H completion (%) 100 66 27 0 Approval based on phase II trial (%) 33 0 73 78 Median development time (years) 8.4 7.8 8.8 5.2

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Lee, Alfred I., Leah E. Masselink, Emily Bass, Nathan T. Connell, Ariela L. Marshall, and Clese E. Erikson. "Mentorship Experiences Among Second-Year U.S. Hematology/Oncology Fellows in the 2019 ASH Hematology/Oncology Fellows Survey." Blood 134, Supplement_1 (November 13, 2019): 2124. http://dx.doi.org/10.1182/blood-2019-132252.

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Mentorship Experiences Among Second-Year U.S. Hematology/Oncology Fellows in the 2019 ASH Hematology/Oncology Fellows Survey Introduction: The majority of fellows graduating from U.S. hematology/oncology training programs pursue careers incorporating both fields, albeit with a greater focus on medical oncology than on hematology. Over the past 15 years, the number of physicians in the U.S. identifying as hematologists or seeking certification in hematology has been dwarfed by those identifying as medical oncologists or seeking oncology certification, with only a small percentage of fellows having a primary interest in benign hematology. In response to these concerns, in 2017 the American Society of Hematology (ASH) launched a multiyear study of the U.S. hematology workforce in clinical practice, research, and training in collaboration with the Fitzhugh Mullan Institute for Health Workforce Equity at the George Washington (GW) University. The initial phase of the ASH workforce study was a survey of over 1800 hematology/oncology fellows conducted in 2018, which identified clinical exposure to hematology during training, research experiences, and mentorship to all be positively and strongly associated with career interest in hematology. A follow-up survey of second-year hematology/oncology fellows was competed in 2019, focusing on career interests, mentorship, and job expectations. The present study reports findings of second-year fellows' perceptions regarding mentorship. Methods: The 2019 Hematology/Oncology Fellows Survey was developed by ASH and GW investigators. Survey questions asked about fellows' career and research interests, clinical exposure during training, mentorship, and perceptions of job security and availability after fellowship. Mentorship questions focused on specific mentorship activities (e.g., coauthoring papers, participating in research projects, developing networking, career advice), perceived mentorship needs, and overall satisfaction with mentorship. The survey was pilot-tested in a small group of second-year hematology/oncology fellows. The final survey was sent electronically to second-year fellows in U.S. hematology/oncology fellowship programs (n = 735) in the spring of 2019 using Qualtrics. Descriptive analyses were performed using Stata 15. Results: Among 212 second-year fellows with complete responses (28.8% response rate), 5.2% declared a primary interest in benign hematology, 20.8% malignant hematology, 30.7% solid tumor oncology, and the remainder some combination of hematology and oncology. The vast majority of survey respondents (83.3%) intended to dual board in hematology and oncology. About one-third (31.9%) reported having a new or continuing mentor in benign hematology during their second year of fellowship, compared to 51.2% in malignant hematology and 60.8% in solid tumor oncology. Less than half of all fellows (45.4%) indicated that their training program had a formal mentorship program. When asked to indicate domains where they wanted more support from mentors, second-year fellows prioritized career development strategies (69.9%), job options (43.7%), optimizing fellowship experiences (41.3%), manuscript review prior to submission (19.4%), clinical trial design review (17.5%), and grant review prior to submission (17.5%). The vast majority of fellows expressed a definite (69.7%) or possible (8.7%) interest in interacting with a mentor virtually via Facebook, Skype, email, or other media if in-person mentorship meetings were not an option. Conclusions: Second-year hematology/oncology fellows in the U.S. reported a wide range of mentorship needs and interests. Most second-year fellows believe they could use more advice from mentors about career development strategies. Few fellows have a primary interest in benign hematology, and the percentage of fellows who report having mentors in benign hematology is lower than malignant hematology or solid tumor oncology. The vast majority of fellows are interested in virtual mentorship if local mentorship is not available. Further expansion of existing mentorship systems and the development of new mentorship models including virtual mentorship may improve the mentorship experience for fellows. Disclosures Connell: Michael H. Flanagan Foundation: Membership on an entity's Board of Directors or advisory committees.

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Inglut, Collin, Kyle Kausch, Alan Gray, and Matthew Landrigan. "Rejuvenation of Stored Red Blood Cells Increases Oxygen Release Capacity." Blood 128, no. 22 (December 2, 2016): 4808. http://dx.doi.org/10.1182/blood.v128.22.4808.4808.

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Abstract Introduction: The goal of a red blood cell (RBC) transfusion is to treat anemia and improve oxygen delivery to tissues (Sharma 2011). RBC metabolic changes during liquid storage increases the affinity of hemoglobin for oxygen by depletion of 2,3-diphosphoglycerate (2,3-DPG). This change reduces the partial pressure of O2 where the oxygen tension of hemoglobin is 50% saturated (p50). Transfusion of stored RBCs manifests immediate deficits in patient 2,3-DPG concentration after surgery with incomplete in vivo restoration 72 hours post-surgery (Scott 2016). This change may bring into question the efficiency of peripheral oxygen unloading of liquid stored RBCs following transfusion. Ex-vivo rejuvenation of allogeneic RBCs increases the levels of ATP and 2,3-DPG and increases the p50 of stored RBCs by right-shifting the Oxyhemoglobin Dissociation Curve (ODC) (Dennis 1979). RBC Oxygen Release Capacity (ORC) is determined by the percent of oxygen removed from hemoglobin across the arterial (100 mmHg O2) - venous (40 mmHg O2) pressure gradient (Li 2016). The objective was to evaluate the changes in 2,3-DPG and p50 during routine blood bank storage for 35 days and the impact on ORC after RBC rejuvenation. Methods: Five (5) units of human whole blood were collected in CPD, processed into leukocyte reduced RBC units and stored in an additive solution (AS-1). Nearly fresh RBC were obtained from a local blood center after days 3 - 6 of storage at 1-6 °C and then stored up to 35 days at 1-6 °C. A ten (10) mL aliquot was withdrawn from each unit on the day of receipt, then on Days 7, 14, 21, 28, and 35. Each aliquot was split equally by volume into Control (untreated) and Rejuvenated Groups (n=5 per group). The Rejuvenated samples (5 mL) were incubated with 0.8 mL rejuvesol™ Solution (Zimmer Biomet) in a dry air blood warmer (Sarstedt SAHARA-III) for one hour at 37 °C. Complete blood counts (CELL-DYN 3700), ODC (TCS Scientific Corp Hemox-Analyzer), and 2,3-DPG (Roche) on perchloric acid extracts were collected. The ORC was calculated from the ODC as previously described (Li 2016). Results: Five (5) units of CPD/AS-1 RBC units were received less than one week post-donation (5.0 ± 1.2 Days). As expected in the Control Group aliquots (n = 5), 2,3-DPG concentration and the p50 value declined significantly (p < 0.001, ANOVA) from Day 7 through Day 35 (Figure 1). Rejuvenated Group aliquots exhibited a significant increase in 2,3-DPG concentration and improved p50 (p < 0.001, t-test) at each storage interval after incubation with rejuvesol Solution compared to untreated Control aliquots (Figure 1). RBC rejuvenation shifted the ODC to the right (Figure 2) and significantly increased the ORC compared to Control aliquots (Figure 3). The ORC of Rejuvenated aliquots did not decline significantly with storage duration (p = 0.11, ANOVA) while Control aliquots were significantly impacted with storage duration (p < 0.001, ANOVA). Conclusion: Reduction in ORC with storage duration of unrejuvenated RBCs suggests impaired oxygen tissue delivery occurs with stored RBCs to the tissue microenvironment. Transfusion practices designed to increase hemoglobin concentration may be less effective with increased RBC age because of reduced oxygen release capacity. These in vitro results confirm previous reports regarding 2,3-DPG changes during storage and treatment with rejuvenation (Valeri 2000). Additional research is proposed to confirm these observations on full RBC units, the clinical impact of reduced oxygen release capacity, and what impact RBCs with a superphysiological ORC have on the tissue microenvironment. Figure 1 RBC p50 (mm Hg) and 2,3-DPG concentration (mmol/g Hb) for paired Rejuvenated and Control groups after storage for 3-6, 7, 14, 21, 28, and 35 days. 2,3-DPG and p50 values were significantly different between groups at each time-point (p < 0.001, t-test). Figure 1. RBC p50 (mm Hg) and 2,3-DPG concentration (mmol/g Hb) for paired Rejuvenated and Control groups after storage for 3-6, 7, 14, 21, 28, and 35 days. 2,3-DPG and p50 values were significantly different between groups at each time-point (p < 0.001, t-test). Figure 2 A representative ODC for a RBC aliquot stored for 21 days (Gray) and the "right-shift" of the curve with rejuvenation (Black) used to determine the ORC. The two vertical dashed lines represent the venous PO2 (40 mmHg) and arterial PO2 (100 mmHg). The solid line represents a typical p50 value of Control and Rejuvenated aliquots. Figure 2. A representative ODC for a RBC aliquot stored for 21 days (Gray) and the "right-shift" of the curve with rejuvenation (Black) used to determine the ORC. The two vertical dashed lines represent the venous PO2 (40 mmHg) and arterial PO2 (100 mmHg). The solid line represents a typical p50 value of Control and Rejuvenated aliquots. Figure 3 RBC ORC for paired Rejuvenated and Control groups after storage for 3-6, 7, 14, 21, 28, and 35 days. ORC was significantly different between groups at each time-point (p < 0.05, t-test). Figure 3. RBC ORC for paired Rejuvenated and Control groups after storage for 3-6, 7, 14, 21, 28, and 35 days. ORC was significantly different between groups at each time-point (p < 0.05, t-test). Disclosures Inglut: Zimmer Biomet: Employment. Kausch:Zimmer Biomet: Employment. Gray:Zimmer Biomet: Employment. Landrigan:Zimmer Biomet: Employment.

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Loschi, Michael, Rinzine Sammut, Edmond Chiche, and Thomas Cluzeau. "FLT3 Tyrosine Kinase Inhibitors for the Treatment of Fit and Unfit Patients with FLT3-Mutated AML: A Systematic Review." International Journal of Molecular Sciences 22, no. 11 (May 30, 2021): 5873. http://dx.doi.org/10.3390/ijms22115873.

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FLT3-mutated acute myeloid leukemia accounts for around 30% of acute myeloid leukemia (AML). The mutation carried a poor prognosis until the rise of tyrosine kinase inhibitors (TKIs). New potent and specific inhibitors have successfully altered the course of the disease, increasing the complete response rate and the survival of patients with FLT3-mutated AML. The aim of this article is to review all the current knowledge on these game-changing drugs as well as the unsolved issues raised by their use for fit and unfit FLT3-mutated AML patients. To this end, we analyzed the results of phase I, II, III clinical trials evaluating FLT3-TKI both in the first-line, relapse monotherapy or in combination referenced in the PubMed, the American Society of Hematology, the European Hematology Association, and the Clinicaltrials.gov databases, as well as basic science reports on TKI resistance from the same databases. The review follows a chronological presentation of the different trials that allowed the development of first- and second-generation TKI and ends with a review of the current lines of evidence on leukemic blasts resistance mechanisms that allow them to escape TKI.

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Leisch, Michael, Michael Pfeilstöcker, Reinhard Stauder, Sonja Heibl, Heinz Sill, Michael Girschikofsky, Margarete Stampfl-Mattersberger, et al. "Adverse Events in 1406 Patients Receiving 13,780 Cycles of Azacitidine within the Austrian Registry of Hypomethylating Agents—A Prospective Cohort Study of the AGMT Study-Group." Cancers 14, no. 10 (May 17, 2022): 2459. http://dx.doi.org/10.3390/cancers14102459.

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Background: Azacitidine is the treatment backbone for patients with acute myeloid leukemia, myelodysplastic syndromes and chronic myelomonocytic leukemia who are considered unfit for intensive chemotherapy. Detailed reports on adverse events in a real-world setting are lacking. Aims: To analyze the frequency of adverse events in the Austrian Registry of Hypomethylating agents. To compare real-world data with that of published randomized clinical trials. Results: A total of 1406 patients uniformly treated with a total of 13,780 cycles of azacitidine were analyzed. Hematologic adverse events were the most common adverse events (grade 3–4 anemia 43.4%, grade 3–4 thrombopenia 36.8%, grade 3–4 neutropenia 36.1%). Grade 3–4 anemia was significantly more common in the Registry compared to published trials. Febrile neutropenia occurred in 33.4% of patients and was also more common in the Registry than in published reports. Other commonly reported adverse events included fatigue (33.4%), pain (29.2%), pyrexia (23.5%), and injection site reactions (23.2%). Treatment termination due to an adverse event was rare (5.1%). Conclusion: The safety profile of azacitidine in clinical trials is reproducible in a real-world setting. With the use of prophylactic and concomitant medications, adverse events can be mitigated and azacitidine can be safely administered to almost all patients with few treatment discontinuations.

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